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Файл:Antibiotics. Study aid
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41
Polymyxin M, polymyxin B (fig. 17) — polymyxins used in medicine.
Fig. 16. Structure оf Fusafungin
Fig. 17. Structure оf polymyxin B
Mechanism of bactericidal action of polymyxins — increase in the
permeability of the cell membrane:
PFR — interaction with anionic sites of the cell membrane of a
microorganism;
the membrane structure is damaged (detergent-like effect);
the permeability of the cell membrane of the microorganism increases for
both intra- and extracellular components;
bactericidal action develops.
Selectivity of antimicrobial action of polymyxins:
cells of skin and mucous membranes of animals and humans have better
protection from the detergent-like action of polymyxins compared to microbes;
antimicrobial selectivity of polymyxins is low.
Spectrum of antimicrobial action of polymyxins:
gram-negative bacteria (E. coli, salmonella, shigella, klebsiella, yersinia,
enterobacteria, H. influenzae);
Pseudomonas aeruginosa;
they are effective against non-multiplying pathogens (see the mechanism of
bactericidal action of polymyxins);
all types of proteus (a specific feature), serrations, gram-positive cocci,
anaerobes are resistant;
resistance develops quite quickly and is cross-related to all drugs of the
group.
42
Pharmacokinetics of polymyxins:
They are not absorbed from the surface of the skin and mucous membranes,
including the gastrointestinal tract.
They do not penetrate the blood-brain barrier at parenteral introduction;
hardly penetrate tissue barriers; have low concentrations in pleural and synovial
fluids; may accumulate in the blood.
They are distributed only in the extracellular environment.
They are quickly inactivated in pus.
They are metabolized in the liver and excreted by the kidneys.
Indications of polymyxins administration:
infections caused by polyresistant gram-negative bacteria, including
P. aeruginosa;
infectious eye diseases;
polymyxin M is used topically to treat infected wounds and burns, abscesses
and other lesions caused by Pseudomonas aeruginosa and other microorganisms
sensitive to this antibiotic;
polymyxin M is prescribed orally for the rehabilitation of the gastrointestinal
tract against bacillary dysentery, food toxicoinfections, enteritis; it is also used before
abdominal surgery;
polymyxin B sulfate is used against sepsis, pneumonia, pyelonephritis,
cystitis, salmonellosis.
Undesirable effects of polymyxins:
severe nephrotoxicity resulting in an increase in creatinine and urea levels in
the blood, proteinuria and hematuria, especially at parenteral introduction;
neurotoxic effect with symptoms of damage to the central and peripheral
nervous system (paresthesia, numbness and tingling of the skin around the mouth,
dizziness, weakness, etc.);
neuromuscular block (intravenous introduction of calcium chloride and
anticholinesterase drugs is necessary);
allergic reactions often resulted in anaphylactic shock.
Contraindications of polymyxins:
allergic reactions to polymyxins;
pregnancy, lactation;
renal failure, myasthenia gravis, botulism;
the use of muscle relaxants and general anesthetics.
43
2.11. FUSAFUNGIN
Fusafungin is a polypeptide antibiotic produced by Fusarium lateritium.
The spectrum of antimicrobial action covers streptococci of group A,
S. pneumoniae, Staphylococcus spp., some strains of Neisseria spp., some anaerobes,
as well as Mycoplasma spp., fungi of the genus Candida.
It is practically not absorbed from the surface of the mucous membrane of the
respiratory tract.
It is used only topically against infectious and inflammatory diseases of the
respiratory tract: rhinitis, rhinopharyngitis, tracheitis, laryngitis, tonsillitis, condition
after tonsillectomy, sinusitis, bronchitis.
Undesirable effects: dryness of the mucous membranes of the respiratory
tract, paresthesia or sneezing, local allergic reactions (swelling and hyperemia of the
skin and mucous membranes), bronchospasm.
Contraindications: hypersensitivity, age up to 2.5 years old due to the risk of
laryngospasm.
2.12. POLYENES
Polyene antibiotics are antibiotics containing at least three isolated or
conjugated double bonds of carbon atoms.
Mechanism of fungicidal action of polyene antibiotics:
PFR — interaction with ergosterol in the cell membrane of a fungal cell;
the spatial orientation of ergosterol in the cell membrane of a fungal cell is
disturbed;
the permeability of the cell membranes of the fungal cell increases;
a fungicidal effect develops.
Mechanism of fungicidal action of amphotericin B:
PFR — interaction with ergosterol in the cell membrane of a fungal cell;
the ergosterol-amphotericin B complex is embedded in the membrane of a
fungal cell;
an extremely low-selective channel appears in the membrane of a fungal
cell, through which its contents release from the cell;
a fungicidal effect develops.
44
Selectivity of antimicrobial action of polyene antibiotics:
ergosterol is absent in cell membranes of humans and animals, cholesterol
performing its function;
antimicrobial selectivity of polyenes is moderate.
Classification of polyenes by method of application:
nystatin, levorin — drugs used topically;
amphotericin B — drugs, the use of which is possible for resorptive action.
2.13. GRISEOFULVIN
Griseofulvin (fig. 18) is an antifungal antibiotic; a benzofuran derivative
produced by Penicillium nigricans and Penicillium griseofulvum.
Fig. 18. Structure оf griseofulvin
Mechanism of fungistatic action of griseofulvin:
PFR — interaction with microtubule proteins of the spindle of
dermatomycetes division;
chromosome divergence during mitosis is damaged;
mitosis at the metaphase stage is delayed;
a fungistatic effect develops.
Selectivity of the antimicrobial action of griseofulvin:
the microtubule proteins of the division spindle in dermatomycetes and
humans differ in structure;
the concentration of griseofulvin in the germinal layer of the epidermis,
namely in the focus of dermatomycosis, is maximum;
selectivity of antifungal action of griseofulvin is high.
45
Pharmacokinetics of griseofulvin:
It specifically binds to keratin during its formation in the precursors of
keratinocytes of the skin, hair and nails, due to which it selectively accumulates in the
germinal layer of the epidermis.
The entire epidermis is replaced by keratin-containing epidermis at
prolonged (at least 8 months) use, which during cell differentiation bound to
griseofulvin and became resistant to fungal invasion.
It is administered orally, topical action is ineffective.
46
3. UNDESIRABLE EFFECTS OF CHEMOTHERAPY
Classification of undesirable effects of chemotherapy by occurrence
mechanism:
toxic and irritating effects;
allergic effects;
biological effects.
Neurotoxic effects of antibiotics
Effect
Medications
hallucinations, convulsions, increased
muscle tone
penicillins
damage to the auditory branch of the
VIII pair of cranial nerves
monomycin, kanamycin, neomycin,
streptomycin, florimycin, ristomycin
lesion of the vestibular branch of the
VIII pair of cranial nerves
streptomycin, florimycin, kanamycin,
neomycin, gentamicin
optic nerve damage
streptomycin, chloramphenicol,
cycloserine, polymyxins
polyneurites
streptomycin, polymyxin,
amphotericin B, cycloserine
neuromuscular block
aminoglycosides, polymyxins
Toxic effects of antibiotics (except neurotoxic)
Effect
Preparations
nephrotoxic
cephaloridin, cephalotin,
aminoglycosides, polymyxins, expired
tetracyclines
hepatotoxic
tetracyclines, rifampicin, griseofulvin,
streptomycin, amphotericin B
suppression of hematopoiesis
chloramphenicol, amphotericin B
embryotoxic and fetotoxic
aminoglycosides, tetracyclines,
chloramphenicol
47
Allergic effects of antibiotics
Allergies may occur when using any antibiotic.
They most often occur when using penicillins and cephalosporins.
They usually appear on the skin (urticaria, itching, dermatitis); other types
are less common.
Anaphylactic shock — a life-threatening undesirable effect — is especially
characteristic when using penicillins.
Biologically undesirable effects of antibiotics
Dysbiosis (dysbiocenosis) is an unhealthy change in the normal bacterial
ecology of a part of body when natural flora is thrown out of balance; variation from
the normal composition of the microflora of the gut.
Dysbiosis usually occurs after taking chemotherapeutic agents as a result of
natural microflora suppression and activation of pathogenic and conditionally
pathogenic flora resistant to this chemotherapeutic agent.
Dysbiosis is most prominent in the digestive tract or on skin but can also occur
on any exposed surface or mucous membranes of the oral cavity or vagina (thrush);
the infection may get into the blood that results in hematogenic dissemination.
Severity of intestinal dysbiosis:
I degree — functional disorders;
II degree — clinical picture of enteritis, colitis, gastritis;
III degree — transient bacteremia.
Directions of combatting against intestinal dysbiosis:
prescribing probiotics to restore microflora deficiency;
prescribing probiotics to stimulate the growth of microorganisms of the
intestinal normoflora;
administering bacteriophages or antibiotics to inhibit the growth and
reproduction of pathogenic microorganisms;
increasing of the body’s immune forces and suppression of hypovitaminosis;
using enzyme preparations to improve digestion;
adsorption of bacteria, toxins, allergens and gases.
48
TEST AND TASKS
TEST
1. Mechanism of anti-microbial action of azithromycin …
A. violation of the synthesis of the cell wall of bacteria;
B. violation of the permeability of the cytoplasmic membrane;
C. inhibition of protein synthesis on ribosomes;
D. increased membrane permeability and impaired protein synthesis.
Answer: C.
2. Side effects of gentamicin …
A. anaphylactic shock;
B. ototoxicity, muscle relaxation;
C. erythrocyte hemolysis;
D. oppression of hematopoiesis, gray collapse in children.
Answer: B.
3. Chloramphenicol may cause in newborns …
A. crystalluria;
B. deafness;
C. gray collapse;
D. arthropathy.
Answer: C.
4. Side effects of tetracycline …
A. anaphylactic shock;
B. ototoxicity, muscle relaxation;
C. erythrocyte hemolysis;
D. catabolic effect, teratogenicity, staphylococcal superinfection.
Answer: D.
5. Are sensitive to benzilpenicillin and erythromycin …
A. shigella;
B. salmonella;
C. pathogenic cocci;
D. mycobacteria.
Answer: C.
49
TASKS
Task 1. Identify antibiotics A, B, C, D, E, F (Ampicillin, Carbenicillin,
Benzylpenicillin, Azlocillin, Oxacillin, Ticarcillin).
Drugs
Resistance
to gastric
acid
Absorbtion in
gastrointestinal
tract, %
Resistance to
penicillinase
(staphylococcus
β-lactamase)
Antimicrobial spectrum
Gram-
positive
microorganisms
Gram-
negative
microorganisms
А – 20–30
– +
B + 20–30
+ +
C + 30–40
– + +
D – 0 – +
+*
E – 0 – +
+*
F – 0 – +
+*
* Active against Pseudomonas aeruginosa and various kinds of proteus — both indolpositive (P. vulgaris, P. morganii, P. rettgeri) and indol-negative (P. mirabilis).
Note: plus — presence of a certain feature, minus — its absence.
Task 2. Determine the semi-synthetic penicillins A, B, C (Ampicillin,
Oxacillin, Azlocillin).
Properties
Drugs
А В С
Spectrum of action
Wide
+ +
Predominantly gram-positive
microorganisms
+
Activity in relation Pseudomonas
aeruginosa
– – +
Stability in the acidic environment of the stomach
+ + –
Resistance to β-lactamases of gram-positive microorganisms
- + –
50
Task 3. Identify the drugs.
1. Semi-synthetic antibiotic. Does not break down in the acidic environment of
the stomach. It is used internally. Active against gram-positive microorganisms,
which are affected by benzylpenicillin. Affects gram-negative microorganisms
(salmonella, Escherichia coli, Proteus, etc.).
2. Antibiotic of the β-lactam antibiotic group. It is used when it is necessary to
create a long-term therapeutic concentration in the blood. Indicated for the prevention
and treatment of rheumatism, syphilis. Administered intramuscularly, duration of
action up to 7 days. It is destroyed by penicillinase.
3. Semisynthetic penicillin, acid-resistant, resistant to penicillinase. It is the
antibiotic of choice for staphylococcal infections resistant to benzylpenicillin. Side
effects: allergic reactions, dyspeptic disorders. It is administered orally and
parenterally.
Task 4. Establish compliance of drugs with their group affiliation.
Drugs
Group
Imipenem
Aminoglycosides
Azlocillin
Aminopenicillins
Vancomycin
Glycopeptide antibiotics
Amikacin
Carboxypenicillins
Carfecillin
Lincosamides
Clindamycin
Macrolides
Nystatin
Polyene antibiotics
Terbinafine
Tetracyclines
Ofloxacin
Ureidopenicillins
Azithromycin
Fluoroquinolones
Doxycycline
Carbopenems
Amoxicillin
Cephalosporins
Ceftriaxone
Allylamines
Task 5. Determine the group of antibiotics (A, В, С, D) by the mechanism
of action.
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