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Файл:Antibiotics. Study aid
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Indications of aztreonam administration.
Reserve drug against infections caused by aerobic gram-negative bacteria:
urinary tract infections (pyelonephritis, cystitis, urethritis, prostatitis);
respiratory tract infections (pneumonia, pleural empyema);
meningitis;
sepsis;
skin and soft tissue infections;
intraabdominal infections;
postoperative infections.
Undesirable effects of aztreonam: undesirable effects common to all β-lactam
antibiotics.
Contraindications: allergic reaction to aztreonam or other β-lactam antibiotics
in the anamnesis.
2.2. GLYCOPEPTIDES
Glycopeptides are antibiotics with the structure of glycopeptides
(peptidoglycans), namely peptides that contain carbohydrate moieties (glycans)
covalently attached to the side chains of the amino acid residues that constitute the
peptide.
Vancomycin (fig. 6), teicoplanin — glycopeptides used in medicine.
Fig. 6. Structure оf vancomycin
Points of glycopeptides efficiency (fig. 7):
cell wall synthesis;
permeability of the cytoplasmic membrane;
RNA synthesis.
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The last two mechanisms are practically not studied; they have no clinical
significance because were noted only in in vitro investigations.
Fig. 7. Points of glycopeptides efficiency
Mechanism of bactericidal action of glycopeptides — cell wall destroy:
PFR — interaction with acyl-D-alanyl-D-alanine in the side amino acid
chains of murein in the periplasm of a microbial cell;
transpeptidase destroys the closure of the amino acid bridge;
defects in the cell wall appear;
the permeability of the cell wall of the microorganism increases;
bactericidal action develops.
Selectivity of antimicrobial action of glycopeptides:
no cell wall in animals and humans; D-alanine is not involved in
metabolism;
glycopeptides have a high selectivity of antimicrobial action.
Spectrum of glycopeptides’ antimicrobial action:
gram-positive aerobic and anaerobic microorganisms: staphylococci
(including MRSA), streptococci, pneumococci, enterococci, peptostreptococci,
listeria, corynebacteria, clostridia (including C. difficile);
gram-negative microorganisms are resistant to glycopeptides.
Indications of glycopeptides administration:
polyresistant strains of staphylococci and streptococci;
pseudomembranous colitis caused by C. difficile, including its onset due to
the use of lincosamides;
infections caused by MRSA.
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Undesirable effects of glycopeptides:
red neck syndrome;
nephrotoxicity;
ototoxicity;
hepatotoxicity.
Contraindications:
allergic reaction to glycopeptides;
I trimester of pregnancy;
breastfeeding.
Conditions of glycopeptides administration:
strict calculation of the dose per body weight and following of the dosage
regime;
performing of therapeutic monitoring;
conducting audiometry and monitoring the functions of the vestibular
apparatus;
determination of creatinine level in blood plasma.
2.3. MACROLIDES
Macrolides are antibiotics with a macrocyclic lactone ring associated with
carbohydrate residues in their structure (fig. 8, 9).
Fig. 8. Structure оf 14-membered
midecamycin
Fig. 9. Structure оf 16-membered
macrolide macrolide roxitromycin
Azalides are macrolides containing a nitrogen atom in the structure of the
lactone ring (fig. 10).
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Fig. 10. Structure оf аzithromycin
Mechanism of bacteriostatic action of macrolides — inhibition of protein
synthesis:
PFR — interaction with the enzyme peptidtranslase on a large subunit of the
ribosome of a microbial cell;
destroyed transfer of an amino acid to a new polypeptide growing on the
ribosome;
stoppage of protein synthesis in the microbial cell;
development of bacteriostatic action.
Selectivity of antimicrobial action of macrolides:
the large subunit of the human ribosome differs from the microbial one;
macrolides have a higher selectivity of antimicrobial action;
microorganisms of the family Pseudomonas spp. and Acinetobacter spp.
have a natural resistance to macrolides.
Classification of macrolides by chemical structure due to the number of
atoms in the ring:
with a 12-membered ring — metimycin, neomethimycin, litrin;
with a 14-membered ring — erythromycin, oleandomycin, roxithromycin,
dirithromycin, clarithromycin, flurithromycin, davercin;
with a 15-membered ring (azalides): azithromycin;
with a 16-membered ring — josamycin, kitazamycin, spiramycin,
rokitamycin, midecamycin;
with a 17-membered ring — lancacidin complex.
Representatives of groups with a 12- and 17-membered ring are not used in
clinical practice.
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Classification of macrolides by origin:
natural — erythromycin, oleandomycin, josamycin, kitazamycin,
spiramycin;
semi-synthetic — roxithromycin, dirithromycin, clarithromycin,
flurithromycin, davercin, rokitamycin, midecamycin.
Classification of macrolides by the spectrum of chemotherapeutic action
and duration of antimicrobial effect:
I generation — erythromycin, oleandomycin;
II generation — roxithromycin, spiramycin, josamycin;
III generation (azalides) — azithromycin.
Macrolides of the first generation:
The spectrum of antimicrobial action includes staphylococci, except RSA,
streptococci, pneumococci, C. diphtheriae, listeria, M. catarrhalis, B. pertussis,
Campylobacter, moraxella, legionella, chlamydia, mycoplasma, spirochaetes.
The duration of antimicrobial action lasts 6 hours; the frequency of
administration should be not less than 4 times a day.
They are the drugs of choice against diphtheria, whooping cough,
campylobacteriosis (enteritis, sepsis, intrauterine lesions), legionellosis (pneumonia
or Pontiac fever), mycoplasmosis as well as streptococcal infections in patients with
penicillin allergy.
Macrolides of the second generation:
Clarithromycin has the same spectrum of antimicrobial action as that of
macrolides of the first generation plus H. pylori, atypical mycobacteria (M. avium,
etc.), H. influenza.
Spiramycin and roxithromycin have the same efficient spectrum of
erythromycin and act on toxoplasmas and cryptospores; they are used to treat
toxoplasmosis and cryptosporidiosis.
The length of antimicrobial action is 8-12 hours due to the drug; the
frequency of administration should be not less than 2-3 times a day.
They are the drugs of choice against chlamydia (trachoma, conjunctivitis,
urogenital infections, venereal lymphogranuloma), concomitant infections with AIDS
caused by atypical mycobacteria, cholecystitis, cholangitis, enteritis, colitis.
Clarithromycin is widely used for H. pylori eradication in gastric and
duodenal ulcers.
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Macrolides of the third generation:
Azalides are the third generation of macrolides.
Azithromycin surpasses macrolides of I and II generations in the activity
against H. influenzae, N. gonorrhoeae and H. pylori; besides, it is active against some
protozoa (T. gondii, Cryptosporidium spp.).
The duration of antimicrobial action is 24 hours; the frequency of
administration should be at least once a day.
It is the drug of choice against orodental infections, skin and soft tissue
infections, syphilis in case of allergy to penicillins; it is also used to prevent atypical
mycobacteriosis in AIDS.
Pharmacokinetics of macrolides:
Erythromycin is not fully absorbed into the gastrointestinal tract, its
bioavailability being significantly reduced in the presence of food. The food less
influences the absorption of azithromycin, roxithromycin and midecamycin, though it
does not affect the bioavailability of josamycin, clarithromycin and spiramycin.
They easily penetrate into the area of inflammation, bile, tonsils, lungs,
paranasal sinuses, while azithromycin can also reach the prostate gland and urinary
tract.
They poorly pass through the blood-brain and blood-ophthalmic barriers.
They get into the placenta and breast milk.
They easily penetrate through cells, including macrophages, where they
promote phagocytosis.
They are excreted mostly with bile through the gastrointestinal tract.
Undesirable effects of macrolides.
Macrolides are one of the safest groups of antibiotics.
Adverse reactions are generally rare:
irritating effect:
– after intravenous administration against phlebitis and thrombophlebitis;
macrolides are administered intravenously only in a diluted form by slow infusion;
– after administered orally against abdominal pain, nausea, vomiting, diarrhea;
it occurs more often while using erythromycin or clarithromycin;
hepatotoxicity is a transient increase in transaminase activity, cholestatic
hepatitis resulting in jaundice, fever, general malaise, weakness, abdominal pain,
nausea, vomiting; more often with the use of erythromycin and clarithromycin;
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neurotoxicity — headache, dizziness, hearing disorders — rarely after
intravenous administration of large doses of erythromycin or clarithromycin;
erythromycin inhibition of microsomal liver enzymes may affect the
pharmacokinetics of taken along with medications;
allergic reactions are uncommon.
Contraindications of macrolides:
allergic reaction to macrolides;
pregnancy (clarithromycin, midecamycin, roxithromycin);
breast-feeding (josamycin, clarithromycin, midecamycin, roxithromycin,
spiramycin).
2.4. LINCOSAMIDES
Lincosamides — antibiotics with amino-containing thioglycosides in their
structure lincomycin (fig. 11), clindamycin are lincosamides used in medicine.
Fig. 11. Structure оf lincomycin
Mechanism of bacteriostatic action of lincosamides — inhibition of protein
synthesis:
PFR — interaction with the peptidtranslase center of the 50S ribosome
subunit that inhibits the arrangement of a protein molecule (see the mechanism of
bacteriostatic action of macrolides);
lincosamides produce bacteriostatic effect on most microorganisms; at
higher concentrations they can bactericidally effect staphylococci, streptococci and
anaerobes.
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Selectivity of antimicrobial action of lincosamides:
the large subunit of the human ribosome differs from the microbial one;
lincosamides have a high selectivity of antimicrobial action.
Spectrum of antimicrobial activity of lincosamides:
aerobic gram-positive cocci (streptococci, staphylococci);
anaerobic non-spore-forming gram-positive bacteria (Actinomyces spp.,
Propionibacterium spp., Eubacterium spp.);
anaerobic microaerophilic gram-positive cocci (Peptococcus spp.,
Peptostreptococcus spp.); microaerophilic streptococci;
anaerobic bacteria (Bacteroides spp., Fusobacterium spp., Clostridium spp.)
and some protozoa (P. falciparum, toxoplasmas);
hardly affect most gram-negative bacteria of the intestinal group;
enterococci, hemophilic bacillus, pseudomonas, neisseria and mycoplasma
are usually resistant;
trichomonas, fungi, viruses are outside the spectrum of action.
Indications of lincosamides administration:
streptococcal tonsillopharyngitis, aspiration pneumonia, lung abscess,
pleural empyema;
infections of skin and soft tissues, including diabetic foot;
bone and joint infections (osteomyelitis);
intraabdominal infections — peritonitis, abscess;
infections of the pelvic organs — endometritis, adnexitis, salpingoophoritis,
non-gonorrheal abscess of the fallopian tubes and ovaries, pelviocellulitis,
postoperative anaerobic vaginal infections;
chloroquine-resistant tropical malaria (clindamycin in combination with
quinine);
toxoplasmosis (clindamycin in combination with pyrimethamine);
severe acne (clindamycin topically);
bacterial vaginitis (clindamycin topically).
Pharmacokinetics of lincosamides:
Lincomycin is poorly absorbed in the gastrointestinal tract — by 30% when
taken on an empty stomach and by 5% when taken after meals. The bioavailability of
clindamycin is 90% and does not depend on food intake.
Lincosamides selectively accumulate in bones and joints, bile.
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They hardly penetrate through the blood-brain barrier.
They penetrate through the placenta and into breast milk.
The duration of antimicrobial action is 6 hours; the frequency of
administration should be at least 4 times a day.
They are metabolized in the liver and excreted mainly through the
gastrointestinal tract.
Undesirable effects of lincosamides:
pseudomembranous colitis;
allergic reactions — rash, redness of the skin, itching. The occurrence of
polymorphic exudative erythema up to Stevens-Johnson syndrome is possible;
hematological reactions — neutropenia, thrombocytopenia;
penetrate into breast milk and inhibit the intestinal flora of the child in
nursing women;
clindamycin damages neuromuscular conductivity.
Contraindications of lincosamides:
diseases of the gastrointestinal tract in the anamnesis: nonspecific ulcerative
colitis, Crohn’s disease, enteritis or colitis due to the use of antibiotics;
allergic reaction to lincosamides;
pregnancy, breast-feeding.
2.5. AMPHENICOLS
Amphenicols are antibiotics containing para-substituted aminobenzenes in
their structure.
Chloramphenicol (fig. 12) — amphenicols used in medicine.
Fig. 12. Structure оf сhloramphenicol
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Mechanism of bacteriostatic action of amphenicols — inhibition of protein
synthesis:
PFR — interaction with a site of a large ribosome subunit of a
microorganism whose function is to interact with the aminoacyl part of the t-RNAamino acid complex;
the interaction of the t-RNA-amino acid complex with a large ribosome
subunit is damaged;
protein synthesis in the microbial cell stops; the ribosome remains bound to
an incomplete polypeptide chain;
bacteriostatic action develops.
Mechanism of the bactericidal action of chloramphenicol — destroy of the
permeability of the cytoplasmic membrane:
PFR — interaction with the site of the large ribosome subunit of Hemophilus
bacillus type B, pneumococcus, or meningococcus;
the synthesis of protein toxins in the microbial cell stops, the ribosome
remains connected to the incomplete polypeptide chain that causes a thickening on it;
the thickening of the molecule blocks the transmembrane pore when an
incomplete toxin attempts to exit the cell through a specialized pore of the cell
membrane of Hemophilus bacillus type B, pneumococcus or meningococcus;
the permeability of the cell membrane of Hemophilus bacillus type B,
pneumococcus or meningococcus is impaired;
the bactericidal effect develops.
Selectivity of antimicrobial action of amphenicols:
the large subunit of the human ribosome differs from the microbial one;
amphenicols have moderate antimicrobial selectivity
Spectrum of chemotherapeutic action of chloramphenicol:
it acts bacteriostatically on streptococci, E. coli, salmonella, shigella,
pathogens of diphtheria, whooping cough, anthrax, brucellosis, plague, mycoplasma,
rickettsia, chlamydia, spirochetes, actinomycetes, anaerobes, including B. fragilis;
it acts bactericidally on hemophilus bacillus type B, pneumococci,
meningococci;
E. coli is sensitive in 30%, staphylococcus — in 45% of cases;
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