General Syst.

Session21
SESSION Antibiotic (1)
Antibiotic 2
Micro 2: 3rd Year

Common Antibiotics
1- β-lactams
➢ This class includes: Penicillin, Cephalosporins, Carbapenems, Monobactams

 Penicillin:
• The 1st natural penicillin is penicillin G or benzyl penicillin.
• Bactericidal.
▪ Active against: G +ve
▪ Not active against: G -ve rods, TB.
▪ Toxicity is low high doses are given.
▪ Cause dose-independent hypersensitivity.

Disadvantages of natural penicillin:

1. Narrow spectrum active against gram + only
2. Inactivated by penicillinase (β-lactamase)
• Penicillin is unstable in solution destroyed by heat, acid, alkali, oxidizing agents
• the dry salt of benzyl penicillin is stable at room temperature.
3. Given parenterally to avoid destruction by stomach acid due to acidity.
4. Rapidly excreted in urine: the blood level falls quickly so dose is injected every 6 hours

Advantages of Semisynthetic penicillins: prepared by acylation of 6-aminopenicillanic acid

1- Penicillinase (β-lactamase)- resistant - e.g. methicillin.

Flucloxacillin:
2- Penicillinase & acid- resistant - antibiotic of choice for oral administration because of its high
absorption.
- Ampicillin, Amoxycillin:
- Are taken orally and are effective against Gram positive and
some of the entero gram negative bacteria
3-Broad spectrum
(Acid-resistant & penicillinase-labile) Carbenicillin:
- active against Pseudomonas aeruginosa
- excreted in urine used in urinary tract infections.

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Cephalosporins
▪ They resemble penicillins structurally with the same mode of action.
▪ Acid-stable
▪ penicillinase-resistant
▪ Broad spectrum of activity

include 5 generations acc. to the spectrum of activity (as the generation gets newer, it has a broader spectrum).

1st G - similar to ampicillin

-  against G +ve & few gram -ve
- susceptibility to β-lactamases
2nd G Cefoxitin
-  against anaerobes.
-  against G-ve
- resistant β lactamases.
3rd G Cefotaxime
 against G-ve
-active against Pseudomonas aeruginosa
- more active (up to 100 fold) than the first and second generation
4th G Cefipime
- last line of defense against resistant infection.
- active against Pseudomonas aeruginosa
- Fourth-generation cephalosporins are zwitterions that can penetrate the outer membrane of
Gram-negative bacteria.
- They also have a greater resistance to β-lactamases than the third-generation cephalosporins.
- Many can cross the blood–brain barrier and are effective in meningitis.

5th G Ceftaroline:
- active against methicillin-resistant Staphylococcus aureus (MRSA)
- active against other Gram-positive bacteria & against Gram-negative bacteria

 Monobactams e.g. Aztreonam (Single-ringed β-lactam)

- Active against G-ve bacteria only
- but no activity against gram-positive bacteria or anaerobes.

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3. Aminoglycosides:
1. Bactericidal to sensitive organisms:
- active against aerobic gram-negative rods.
- Poorly active against gram-positive organisms & no activity against anaerobe or Streptococci
(except when acting synergically with a penicillin).
2. Not absorbed by mouth.
3. Can be nephrotoxic.
4. All are potentially neurotoxic (8th nerve); causing ototoxicity (usually irreversible deafness).
5. little penetration to the cerebrospinal fluid.

- used as a first-line drug against tuberculosis the first effective and cheap drug for initial
treatment of T.B
• Streptomycin:
- its ototoxicity and the  development of resistance  usefulness.
- It is used in combination with isoniazid and rifampicin.
- less toxicity than streptomycin.
• Kanamycin: - It is a second-line drug in the treatment of tuberculosis.
- It is a complex of 3 antibiotics A, B, and C.
- semisynthetic derivative of kanamycin.
• Tobramycin: - active against Pseudomonas strains.
- Marked increase in the resistant P. aeruginosa strains.
- semisynthetic derivative of kanamycin
•Amikacin - with resistance to some types of aminoglycoside-modifying enzymesespecially those
modifying tobramycin and gentamicin.
- more active against P. aeruginosa.
• Gentamicin:
- used in combination with carbenicillin to delay the development of resistance P. aeruginosa.
•Neomycin & - toxic for systemic use.
Framycin - Can be applied topically in the form of powder, cream, ointment, eye or ear drops
- aminocyclitol has widely and successfully used for treatment of gonorrhea caused by penicillin-
• Spectinomycin
resistant gonococci in a single large intramuscular dose.

4. Tetracyclines: Tetracycline, Oxytetracycline, Doxycycline, Minocycline.

• A family of closely related antibiotics with 4-ringed structure.

• Like chloramphenicol (broad spectrum, bacteriostatic).
• Bacterial resistance develops rather readily, and has become increasingly common even in species such as
streptococci.
• Doxycycline and Minocycline (recently introduced tetracycilines) are well absorbed and are slowly excreted
so that a daily dose is sufficient.

Side effects:

• Permanent yellow staining of teeth limits its use for children during the early years of life or to mothers
during the later months of pregnancy.
• Severe liver damage in pregnant women and teratogenic effects on fetus are reasons for avoiding these
drugs during pregnancy.

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Micro 2: 3rd Year
Give reasons: Aminoglycosides can be taken with beta lactams while tetracyclines can’t

5. Chloramphenicol:
- derived from Streptomyces venezuelae, but is now produced synthetically at low cost.

• It has a broad spectrum of activity against a wide range of bacteria, rickettsiae and chlamydiae.
• bacteriostatic effect except with H. influenzae it exerts bactericidal action.
• It is well absorbed orally
• penetrates to the cerebrospinal fluid more readily than any other antibiotics.
• Because of the risk of fatal bone marrow depression (aplastic anaemia), it is only used for certain life threatening
infections e.g. typhoid fever and meningitis due to H. influenzae.
• It is of little value in urinary tract infection because the kidneys excrete it mainly in an inactive form.
• Chloramphenicol drops or ointment are effectively and extensively used for treating eye infections.

6. Lincosamides Clindamycin.

- Semisynthetic derivative of lincomycin

-  well absorbed by mouth
- It closely resembles erythromycin in most of its properties & there is no chemical relationship to
macrolide antibiotics.
- It is most active against gram positive cocci and anaerobes
- an effective alternative to penicillin for use against Str. Pyogenes.
- It penetrates into bone better than most antibioticsused in treatment of osteomyelitis.
- Common side effect is antibiotic associated colitis

7.Macrolides & Azalides

Erythromycin: the most important members of this group.
- It has an antibacterial range similar to that of benzyl penicillin (gram +ve).
- It is a alternative to penicillin in penicillin hypersensitive patients.
a. Macrolides - widely used in pediatrics because it lack of toxicity and its availability in the oral suspension
- Used as a prophylactic drug against whooping cough.
- It is the drug of choice for campylobacter and legionella infections.
Azithromycin: similar action to the macrolides:

b. Azalides: Erythromycin:  intracellular penetration & resistant to the metabolism serum half-life of. (low
rate of administration: 1 dose per day.

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8. Fusidic acid
- It has a steroidal structure with its sodium salt is well absorbed when given by mouth.
- Fusidic acid is apparently free from serious toxic effects
- highly effective against most strains of Staph. aureus, including penicillinase-producers.
- It is particularly good for eradication of staphylococcal infections of bones and joints

Give reasons: Clyndamycin is sometimes prescribed with fusidic acid.

9. Rifampicin
- It is a semisynthetic derivative of one of the naturally occurring rifamycins,.
- The clinical usefulness of natural rifamycins is impaired by their rapid excretion in the bile.
- Rifampicinwell absorbed orally.
- It is bactericidal to gram-positive bacteria, some gram-negative bacteria and is the most potent anti T.B
- it penetrates well into cerebrospinal fluid used in the treatment of tuberculous meningitis
- Its most serious limitation is the speed of development resistance should probably never be used alone.
- Its main side effect is the development of jaundice or gastrointestinal disturbance

Give Reason: Rifampicin can’t be taken alone

10. Polymyxins
• They are bactericidal polypeptide antibiotics derived from Bacillus spp.
• Are effective against Ps. aeruginoea and most other gram-negative rods.
• All are nephrotoxic but the systemic toxicity of polyinyxin B and E is not sufficient to preclude their usecould be
used intramuscularly when necessary.
• They are also used for treatment of intestinal infections since they are not absorbed from the intestine when
given orally.
• They are used in the form of powders and ointments for the treatment of wounds and burns.

Chemotherapeutic

I. Sulfonamides:
- Are bacteriostatic to a wide range of bacteria, cheap.
- It is now of limited and decreasing medical importancebecause of the availability of a more useful antibiotic(s).
- The numerous members of this class differ only in pharmacological characteristics:
➢ they may be classified into 4 groups on the basis of the rapidity with which they are absorbed and excreted.

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Side effects:

- Crystalluria, Hematuria -
- Hypersensitivity reactions: Stevens-Johnson syndrome
- Bone marrow suppression

- e.g. Sulfadiazine and sulfaisoxazole

- These used for treating acute urinary tract infections

Rapidly absorbed, Sulfaisoxaole is much more soluble in urine than sulfadiazine

- in both cases it is advisable that the patient must be given alkalis, such as sodium
rabidly excreted
bicarbonate, and much fluids to prevent crystal deposition in renal tubules and
ureter (crystalluria).
Sulfadiazine is rapidly absorbed and diffuses well into tissues including the cerebrospinal
fluid treatment of meningitis due to sensitive meningococci
•e.g. Sulfamethoxazole
Rapidly absorbed, - It is used in combination with trimethoprim to prevent emergence of resistant strains.
slowly excreted - This synergistic combination useful for many infections, including typhoid fever,
gonorrhea and brucellosis.
e.g. Succinyl- and phthalyl sulfathiazole.
Non-absorbable - for preoperative suppression of bowel microbiota.
sulfonamides - used for bowel infections e.g. bacillary dysentery, but many strains are resistant to
sulfonamides.
e.g. Sulfacetamide.
Topical sulfonamides - It is not used systemically
- highly soluble widely used in the form of eye drops and eye ointment.
*II) Quinolones
- Broad spectrum compounds.

Nalidixic acid: - used for treatment of UTI when renal function is abnormal.
- Resistance develops rapidly.
- side effects such as allergic reactions such as urticaria, photosensitivity
and fever and CNS disturbances such as visual disturbances,
hallucination.
c) Norfloxacin: - 100 times more active than nalidixic acid
- has antipseudomonal activity.

*IV) Nitrofurans: Broad spectrum

a) Nitrofurazone:. Used topically for infected wounds
c) Nitrofurantoin: Used for UTI Given orally is well absorbed
- excreted too rapidly to produce effective plasma levels.
- Not used in case of impaired kidney functions

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Micro 2: 3rd Year

*VI) Imidazoles
1. Antianaerobic e.g. Metronidazole.  the first compound introduced.
o reduced by strict anaerobes, e.g. clostridia and bacteroides to compounds, which bind to DNA causing
strand breakages.
2. Antifungal e.g. Clotrimazole, Econazole, Miconazole and Ketoconazole.
- All are active against yeasts and dermatophytes (tinea)

Antifungal drugs:
I. Topical
A-Polyenes B-Imidazoles
Clotrimazole, Miconazole and
Examples Nystatin and Natamycin
Econazole
Uses Candidiasis not dermatophytes Tinea and candidiasis

II. Systemic:
C-ketoconazole (orally)
Examples A-Amphotericin B B- Flu-cytosine D-Griseofulvin
& Miconazole (intravenously)
For histoplasmosis (a type of lung Accumulates in skin
infection. It is caused by inhibiting
Invasive yeast & dimorphic Invasive yeasts &
Uses inhaling Histoplasma, chronic and dermatophytes.
fungi candidiasis
invasive candidiasis and Used for tinea of the
dermatophytes scalp and nails

Anti tuberculous drugs:

Management of T.B:
1- Treatment with at least 2 drugs to prevent resistance.
2- Patient compliance is necessary.
3- All the contacts of the patients must be screened (X-ray and microbiological tests).

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Micro 2: 3rd Year
 First-line drugs: used in the beginning given orally.

a-Rifampicin The most potent, expensive and cause hepatitis.

b-Isoniazid: (INH) highly effective, cheap, resistant strains cause hepatitis or peripheral neuritis.
c-Ethambutol: In low dose a useful supporting drug.
- use initially 3 drugs in combination (Rifampicin + INH + ethambutol) until the sensitivity test results
are knownIf the organism is sensitive to Rifampicin and INHethambutol is ceased.
- Cough is alleviated and  bacterial number in sputum within 2-3 weeks of treatment onset.

Secondary drugs: less frequently used because of their side effects.

a-Streptomycin: - It has the disadvantage  has to be injected.

b-Pyrazinamide: - good penetration into CSF (tuberculous meningitis).
- used in the initial phase to produce a highly bactericidal effect.
c-Thiacetazone: - usages is limited by its side effects (hepatitis and hemolytic anemia)
- In combination with other drugs, gives highly effective therapy but its general usages
is limited by its side effects
- in respiratory TB: use of 4 drugs in combination (Rifampicin + INH + streptomycin + pyrazinamide)
for 2 months, followed by Rifampicin and INH for further 4-6 months.

Antiviral drugs
- used in the treatment of human viral infections.
- The main problem in designing and developing antiviral agents is the lack of selective toxicity
- Possible sites of attack by antiviral agents include prevention of adsorption or intracellular penetration of
absorbed virus, and inhibition of protein or nucleic acid synthesis.

1-Non selective antiviral agents: Examples

a-Amantadine: inhibits viral uncoating. It is used for prophylaxis against infection with influenza A virus.

b-Iodoxuridine: It inhibits nucleic acid synthesis. It is restricted to topical treatment of herpes-infected eyes.

c- Oseltamvir (tamiflu) and zanamvir now used for influenza type A virus.

2- Selective antiviral agents: Examples

a- Phosphonoacetic acid: It inhibits DNA synthesis of herpes viruses.

b- Interferons: low molecular weight proteinsproduced by virus-infected cellsinducing the infected cell to form a
second protein inhibits the transcription of viral mRNA.

Type 1 interferons Type 2 interferons

are produced by virus-infected cells and confer are produced by stimulated lymphocytes and prevent
protection on neighboring cells spread of viruses from cell to cell.
N.B: -different forms of interferon were used for the treatment of chronic hepatitis C.

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Micro 2: 3rd Year
New antiviral drugs
• Anti hepatitis C drugs:

- Sovaldi: - Inhibits the RNA polymerase that (HCV) uses to replicate its RNA
- harvoni - (mix. of sovldi and other polymerase inhibitor drug)  time of treatment and widen range of
treated genotype.
- Epclusa - newest drug used in June 2016 to treat all genotypes (1-6)

• Anti covid 19 drugs:- Remdesivir:

- a nuceotide analoge prodrug used to treat covid 19.

- by inhibiting RNA dependant RNA polymerase as it allows the addition of only 3 nucleotides stops the
growing RNA & hinders replication.

BACTERIAL RESISTANCE TO ANTIBIOTICS:

• Antibiotic resistance occurs when bacteria develop the ability to beat the drugs.

• Overuse and misuse of antibiotics  development of antibiotic resistance

Types of bacterial resistance:

Intrinsic, inherent or innate resistance Acquired resistance

Chromosomally-mediated. by mutations in chromosome or via HGT (plasmids, transposons)
Independent on previous antibiotic exposure. depend on the previous antibiotic exposure
The intrinsic properties of the M.O are The M.O which was previously sensitive, becomes resistant after
responsible for resisting the AB exposure to certain antibiotic.

3 genetic elements are responsible for acquiring resistance:

- Changes occur in the DNA sequence (point or frame shift) could result in
1. Chromosomal
development of antibiotic resistance through mutation in certain genes
mutations: followed by natural selection.
- Plasmids are circular DNA that exist in the cell separated from the
2. Plasmids: chromosome.
- plasmid can carry a genes encoding
- Acquisition of single plasmid can make bacterium resistant to AB
- They are jumping genetic elements capable of transferring or
transposing independently from one DNA molecule (chromosomes or
3. Transposons:
plasmids) to another.
- The central region of the transposon often codes for antibiotic
resistance genes

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Biochemical mechanisms of resistance:
1. Alteration in membrane structure   permeability to the Antibiotic inhibition of drug uptake.
2. Efflux pumps remove AB from the cytoplasm to the outside.
3. Production of enzymes inactivate AB
4. Alteration in the target site by:
a- Modification of the target site  AB binding.
b- Overproduction of the target site AB concentrations required to exert antimicrobial action.

Mechanism of Example Comment

resistance
• β-lactam antibiotics: Mutational loss of porins
•Aminoglycoside antibiotics: Reduced ability of cells to uptake the drug
Impermeability to
antibiotic •Tetracycline, Fusidic acid and Chloramphenicol: Plasmid-mediated decreased drug accumulation
•Novobiocin, actinomycin, erythromycin and rifampicin: Difficulty in entering Gram-negative
Efflux Tetracyclines Energy-dependent efflux of accumulated drug
• β-lactam antibiotics: β-lactamase Hydrolysis of the β-lactam ring
Enzymatic
•Chloramphenicol: Chloramphenicol acyl transferase (CAT) Conversion to an inactive compound
inactivation
• aminoglycoside: Alteration of the antibiotic by phosphorylation, adenylation or acetylation
β-lactam antibiotics: Altered penicillin binding proteins (PBP)
Sulphonamide: Altered dihydropteroate synthetase
Decreased affinity Trimethoprim: Altered dihydrofolate reductase
of
Fusidic acid: Altered translocation factor
target enzyme
(alteration of the 1. Streptomycin - Altered 30S ribosomal subunit
target 2. Erythromycin - Altered 50S ribosomal subunit
site) 3. Tetracycline - Altered 30S ribosomal subunit
4. Glycopeptides - Altered peptidoglycans precursors with lower affinity (D-Ala-D-Ala)
5. Quinolones - Altered gyrase
6. Rifampicin - Altered RNA polymerase
Overproduction of
1. Sulphonamide • Overproduction of p-amino benzoic acid (PABA)
the target site or
2. Trimethoprim • Overproduction of dihydrofolate reductase
metabolite

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Micro 2: 3rd Year
Resistance to β-Lactams: Acquired resistance by 3 different mechanisms:
1- Reduced of drug permeability.
2- Inactivation of the antibiotic by β-Lactamase
3- Alteration of the target site (Transpeptidase or penicillin binding protein (PBP)

1 . Reduced drug permeability:

- G-ve bacteria can alter the outer membrane porins  the penetration of β-lactams

2. Inactivation of the AB by β-lactamases :

- Bacteria produce β-lactamase hydrolyze the cyclic amide bondpenicilloic acid not bind to PBPs
unable to bind to penicillin-binding proteins
▪ In G-ve bacteria: β-lactamases are found in the periplasmic space
▪ In G+ bacteria: they are secreted extracellularly.

3. Alterations in PBPs: e.g. Example: MRSA (methicillin resistant S.aureus).

- Alteration in PBPs low affinity to β-lactams  Methicillin resistance

- These are causing increasing in hospitalsbecause methicillin resistance is accompanied by
multiple resistance

Multidrug resistance pumps:

- Multiple antibiotic resistance (MAR) to many unrelated antibiotics by efflux
- Mutants resistant to low levels of chloramphenicol, tetracyclines, rifampicin, penicillins and quinolones, due to
impaired uptake of the antibiotics

The problem of antibiotic resistance:

1. It is the most common cause of treatment failure.
2. lead to the use of more expensive and more toxic drugs length of infection & hospital stay.

• The problem is not confined to nosocomial bacteria but also community-acquired pathogens have become
resistant to key antibiotics.

• The appearance of MRSA must serve as a warning signal.

- Vancomycin (or teicoplanin) is often the only antibiotic effective against some MRSA strains.
- Acquisition of vancomycin resistance by MRSA would leave a health disaster. (VRSA strains exist now).

• Pan drug resistant strains of Acinetobacter baumannii endangers the antibiotics.

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Micro 2: 3rd Year
How to overcome bacterial resistance to antibiotics:
Bacterial resistance to antibiotics could be overcome by:

1- Designing new drugs

- unsusceptible to the enzyme attack (β-lactamase resistant penicillin e.g. cloxacillin).
- inactivate the enzyme (β-lactamase inhibitors e.g. clavulinic acid, sulbactam and tazobactam).
2- Development of new antibiotics (modification of an already existing ones.
3- Development of natural peptides with antibacterial activity to overcome the low penetration in case of
Gram-negative bacteria.
4- Drug combinations

Drug combinations:2 antibacterial agents may produce the following responses.

• Synergism, 1 + 1 > 2

• Additive effect, 1 + 1 = 2

• Antagonism (interference), 1 + 1 < 2

• The advantages of clinical synergism:

1. To obtain a wider spectrum of activity for treatment of mixed infections as in life-threatening mixed
anaerobic and aerobic infections exist.
- The use of metronidazole in combination with aminoglycoside essential.
2. To prevent the emergence of resistant organisms
- as in combined anti-TB therapy
- in treatment of Staph. aureus infections with fusidic acid and flucloxacillin.
3. To reduce the dosage of a toxic drug:
- as in treatment of meningitis caused by the fungus: amphotericin with 5-flucytosine.
4. To protect the effect of an antibiotic:
- with β-lactamase inhibitor and an β-lactamase-labile penicillin.

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Micro 2: 3rd Year
Antibiotic policy: Are Guidelines to provide the prescriber with a range of agents appropriate to the patient
needs to ensure the unnecessary use i.e. abuse of antibiotics. In order

1. To prevent the development resistance to antibiotic. 2. To reduce antibiotic toxicity.

3. To reduce the cost of antibiotic use. 4. To provide the patient with optimal antibacterial therapy

we need to consider some general principles:

1- An antibiotic has to be prescribed for a valid reason include the following:

a- Prevention of a bacterial infection:
- as in case of patients with rheumatic fever, they have to be protected during childhood from Streptococcus
pyogenes, penicillin can be for prophylaxis.
b- Pre-operative prophylaxis: before operations involving the intestine, particularly the GIT & reduce the risk of
wound infection.
c- Prophylactic administration of penicillin: for patients at risk of developing gas gangrene as in major trauma.
2- It’s bad to use a broad spectrum AB when the infection can be treated with more specific agent.
3- It’s necessary to isolate the causative organism before treatment is started.
4- it’s essential to use a bactericidal agent not a bacteriostatic oneIn case the patient is immunocompromised or
with bacterial endocarditis
5- In some cases (e.g. TB), it’s necessary to use a combination of antimicrobials  risk of resistance.
6- In case of superficial skin infections it’s important to use a topical antiseptic not systemically.
7- The AB should be given in the proper dose for the long enough period then stop treatment or change to another
drug if the patient is not responding to the initial one.
8- Avoid the use of AB as food supplement for animals to reduce the spread of microbial resistance.
9- To reduce the emergence of AB-resistance in hospitals, use ABs in rotation and keep particular ABs for use only on
special occasions.

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