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Antibiotics. Study aid

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 Mycobacterium of tuberculosis and leprosy, Pseudomonas aeruginosa,

klebsiella, enterococci, citrobacter, enterobacter, acinetobacter, serratii, indoleproducing proteus, protozoa and most fungi are resistant.

Pharmacokinetics of chloramphenicol:

 It readily passes barriers, including intestinal, blood-brain, hematoplacental ones.

 High concentrations are observed in brain tissue, bronchial secretions, pleural and synovial fluids, fetal blood serum, breast milk.

 It is metabolized in the liver. Chloramphenicol biotransformation is slow with its possible accumulation in newborns and patients with severe hepatic insufficiency.

 The half-life in adults is 1.5-3.5 hours; in children it can increase to 6.5 hours; in newborns it may last up to 24 hours or more.

 Chloramphenicol succinate applied parenterally has no antimicrobial

activity. The part of the drug can be excreted before the succinate cleavage, therefore, the concentrations of chloramphenicol in the blood with parenteral, and especially intramuscular administration, may be lower than when taking the same dose orally.

Indications of chloramphenicol administration.

Chloramphenicol should be used only as a reserve drug due to the risk of complications:

 generalized forms of salmonellosis, typhoid;

 rickettsiosis — typhus, Q fever, Rocky Mountain spotted fever;

 highly dangerous infections — plague, tularemia, brucellosis;

 hemophilic infection (meningitis, pneumonia, sepsis);

 severe purulent meningitis, brain abscesses;

 intra abdominal infections, pelvic organ infections;

 gas gangrene.

Undesirable effects of chloramphenicol:

 hematotoxic effect;

 “grey” collapse;

 neurotoxicity, optic neuritis;

 endotoxic shock (was described when patients with syphilis, brucellosis and

typhoid fever were using chloramphenicol);

 irritating effect, gastrointestinal tract lesions;

 dysbiosis, including candidiasis or staphylococcal dermatitis in the presence

of skin diseases;

 allergic reactions (skin rash, urticaria, angioedema).

Contraindications of chloramphenicol:

 pathology of hematopoietic organs;

 allergic reaction to chloramphenicol in the anamnesis;

 kidney and liver diseases;

 pregnancy and lactation;

 newborns;

 eczema, psoriasis.

2.6. TETRACYCLINES

Tetracyclines (fig. 13) are antibiotics containing four fused six-membered cycles in their structure.

Fig. 13. Structure оf tetracyclines

Mechanism of bacteriostatic action of tetracyclines — inhibition of protein synthesis on the ribosome:

 PFR — interaction with a small ribosome subunit site whose function is to interact with the t-RNA-amino acid complex;

 the interaction of tRNA with ribosome is damaged;

 protein synthesis in the microbial cell is destroyed;

 bacteriostatic action develops.

Mechanism of bacteriostatic action of tetracyclines — destroy of metalloproteins formation:

 PFR — interaction with divalent metal ions in the cytoplasm of a microbial cell;

 formation of a chelate complex;

 the inclusion of divalent metals within the metalloproteins of the microbial cell is prevented;

 protein synthesis in the microbial cell is impaired;

 bacteriostatic action develops.

Selectivity of antimicrobial action of tetracyclines:

 There are mechanisms of active transport of tetracyclines into the cell in the membrane of a microbial cell. Therefore, the concentration of the drug in the microorganism exceeds the concentration of the drug in the macroorganism.

 Antimicrobial selectivity of tetracyclines is low.

Classification of tetracyclines by origin:

 biosynthestic — chlortetracycline, tetracycline, oxytetracycline;

 semi-synthetic — morphocycline, doxycycline, vibramycin.

Spectrum of antimicrobial activity of tetracyclines:

 pneumococci, meningococci;

 listeria, H. influenzae, H. ducreyi, yersinia, moraxellae, campylobacter

(including H. pylori), brucella, bartonella, vibrio (including cholera), pathogens of inguinal granuloma (Calymmatobacterium granulomatis), anthrax, plague, tularemia;

 spirochaetes, leptospira, borrelia, rickettsia, chlamydia, mycoplasma,

actinomycetes, some protozoa;

 anaerobes — clostridia (except C. difficile), fusobacteria, P.acnes;

 most strains of bacteroids, E. coli, salmonella, shigella, klebsiella;

 many gonococci are resistant;

 yeast-like fungi or staphylococci usually cause dysbiosis in the treatment of

tetracyclines.

Pharmacokinetics of tetracyclines:

 Taken orally, tetracyclines are readily absorbed, doxycycline easier than tetracycline. The bioavailability of doxycycline does not change, while that of tetracycline decreases by 2 times due to food intake.

 Aluminum hydroxide, calcium, magnesium, iron and zinc salts, bismuth subsalicylate as well as dairy products worsen the absorption of tetracyclines, since the latter form hardly absorbed chelate complexes with two- and trivalent cations.

 Tetracyclines selectively accumulate and stay in the bone tissue for a long time.

 Their concentrations in cerebrospinal fluid are 10–25% of the level in blood serum; concentrations in bile are 5–20 times higher than in blood.

 Tetracyclines easily penetrate through the placenta and get into breast milk.

 The duration of antimicrobial action is 6–12 hours; the frequency of

administration should be 2–4 times a day.

Indications for tetracyclines administration:

 highly dangerous infections — brucellosis, tularemia, cholera, plague,

anthrax;

 rickettsiosis — typhus, Q-fever, Rocky Mountain spotted fever;

 borreliosis — Lyme disease, recurrent typhoid;

 mycoplasmosis;

 chlamydiaoses — trachoma, urethritis, cervicitis, prostatitis;

 gonorrhea (in the presence of sensitivity), syphilis, venereal

lymphogranuloma;

 H. pylori eradication against gastric and duodenal ulcer (tetracycline);

 acne caused by P. acnes;

 wound infection after animal bites;

 prevention of tropical malaria.

Undesirable effects of tetracyclines:

 catabolic effect;

 hepatotoxicity up to the development of fatty degeneration or liver necrosis;

 hemorrhages;

 teratogenic effect, damage to bone formation;

 destroy of the structure of tooth enamel;

 photodermatoses;

 increased intracranial pressure;

 dysbiosis;

 irritating effect, namely ulceration of the intestine, dyspeptic disorders,

destroyed synthesis of vitamins in the colon and damaged absorption of vitamins;

 allergic reactions (urticaria, Quincke’s edema, anaphylactic shock).

Contraindications of tetracyclines:

 children under 12 years of age;

 pregnancy, breastfeeding;

 insufficient liver function;

 anemia, leukopenia.

2.7. AMINOGLYCOSIDES

Aminoglycosides are antibiotics, which include several amino sugars joined with an aminocyclitol core by a glycoside bond.

Mechanism of bacteriostatic action of aminoglycosides — inhibition of protein synthesis in a microbial cell:

 PFR — interaction with a small ribosome subunit near the i-RNA attachment site;

 the interaction of i-RNA with the ribosome is destroyed;

 no initialization of protein synthesis in the microbial cell;

 bacteriostatic action develops.

Mechanism of secondary bactericidal action of aminoglycosides — misreading of protein synthesis in a microbial cell:

 PFR — interaction with a small ribosome subunit near the i-RNA attachment site;

 the interaction of i-RNA with the ribosome is destroyed;

 the triplet codon on the ribosome is misread (with a shift of 1 nucleotide);

 an improper protein is synthesized;

 the cytoplasmic membrane of the microbial cell stops functioning;

 bactericidal action develops.

Classification of aminoglycosides according to the spectrum of

antimicrobial action and resistance to aminoglycosidases

 I generation — streptomycin (fig. 14), kanamycin, monomycin, neomycin;

 II generation — gentamicin (fig. 15);

 III generation — sizomycin, amikacin, tobramycin, netilmycin;

 IV generation — isepamycin.

Fig. 14. Structure оf streptomycin

Fig. 15. Structure оf gentamicin

First generation of aminoglycosides:

 The spectrum of antimicrobial action covers staphylococci, enterococci and

Enterobacteria, including E. coli, Klebsiella spp., Salmonella spp., Shigella spp., Proteus spp., Serratia spp., Enterobacter spp.

 Streptomycin and kanamycin are the drugs of choice against tuberculosis,

plague, tularemia, brucellosis, infectious endocarditis.

 Monomycin is effective against some protozoa.

 Aminoglycosides of the first generation are exposed to the action of 15

enzymes-aminoglycoside.

Aminoglycosides of the second generation:

 They differ from the drugs of the first generation by their efficiency against

P. aeruginosa.

 Do not combat mycobacteria of tuberculosis and protozoa.

 Aminoglycosides of the second generation are exposed to the action of 10

enzymes-aminoglycoside.

 Gentamicin is the drug of choice against complicated infections of the respiratory and urinary systems, intraperitoneal infections, sepsis, peritonitis, meningitis, abscess in the abdominal cavity with an undetected pathogen, postoperative or posttraumatic osteomyelitis.

Aminoglycosides of the third generation:

 Compared with aminoglycosides of the second generation, they have a stronger effect on P. aeruginosa.

 Only 3 enzymes-aminoglycosidases can act on these drugs.

 Amikacin is effective against M. avium and other atypical mycobacteria,

therefore it is used against disseminated infections caused by them in AIDS patients.

Aminoglycosides of the fourth generation:

 Like the spectrum of antimicrobial action of aminoglycosides of III generation, they are also effective against Aeromonas spp., Citrobacter spp., Listeria

spp. and Nocardia spp.

 Isepamycin is an anti-tuberculosis drug like streptomycin and kanamycin being the first generation of drugs.

 Only 3 enzymes-aminoglycosidases can act on these drugs.

 All generations of aminoglycosides are not effective against S. pneumoniae,

S. maltophilia, B. cepacia, anaerobes (Bacteroides spp., Clostridium spp., etc.).

Moreover, the resistance of S. pneumoniae, S. maltophilia and B. cepacia to aminoglycosides can be used to identify these microorganisms.

Pharmacokinetics of aminoglycosides:

 Aminoglycoside molecules as highly polar compounds are poorly soluble in lipids and, therefore, can hardly pass through biological barriers.

 They are practically not absorbed when ingested.

 The introduction of the drug against meningitis is to be endolumbal.

Streptomycin cannot be administered in the same way, streptomycin-chlorocalcium

complex being used instead.

 They neither penetrate into most cells, nor act on intracellularly located pathogens.

 The duration of the antimicrobial action of streptomycin is 12 hours; the frequency of administration should be at least 2 times a day.

 The duration of the antimicrobial action of gentamicin and amikacin is 8 hours; the frequency of administration should be 3 times a day. The duration of isepamycin action may take up to 2 days.

Indications of aminoglycosides administration:

 complicated urinary tract infections — acute pyelonephritis, paranephritis, urosepsis, kidney carbuncle;

 complicated intraperitoneal infections — peritonitis, abscess of the abdominal cavity;

 complicated infections of the respiratory tract — pleuropneumonia;

 postoperative or posttraumatic osteomyelitis;

 sepsis, especially staphylococcal one;

 meningitis.

Undesirable effects of aminoglycosides:

 ototoxic effect:

 the ototoxic effect of aminoglycosides is reversible only against the very

beginning, often causes complete deafness (in children — deaf-dumbness);

 hydrocortisone, indomethacin, furosemide, ethacric acid, cephaloridin,

cyclosporine, amphotericin B enhance the ototoxic effect of aminoglycosides;

 calcium pantothenate weakens the ototoxic effect;

 nephrotoxic effect;

 curare — like action;

 malabsorption in the intestine.

Contraindications to aminoglycosides administration:

 allergic reactions to aminoglycosides;

 pregnancy, breastfeeding;

 liver and kidney insufficiency;

 diseases of the hearing organs;

 neuritis of the auditory nerve.

Conditions of aminoglycosides administering:

 strict calculation of the dose per body weight and following with the dosing regimen; therapeutic monitoring;

 monitoring of the duration of the course of treatment;

 determination of creatinine level in blood plasma;

 performing audiometry before, during and after treatment.

2.8. RIFAMYCINS

Rifamycins are semi-synthetic antibiotics derived from ansamycins produced by Streptomyces mediterranei.

Rifamycin SV, rifampicin — rifamycins used in medicine.

Mechanism of bacteriostatic action of rifamycins — the blockade of DNAdependent RNA polymerase:

 PFR — interaction with DNA-dependent RNA polymerase of a microorganism;

 DNA-dependent RNA polymerase is blocked;

 the synthesis of the microorganism's RNA is inhibited;

 bacteriostatic action develops.

Mechanism of bacteriostatic action of rifamycins — inhibition of the protein synthesis initialization in a microbial cell:

 PFR — interaction with a small ribosome subunit near the i-RNA attachment site;

 the interaction of i-RNA with the ribosome is damaged;

 the misreading of protein synthesis in the microbial cell;

 bacteriostatic action develops.

Selectivity of antimicrobial action of rifamycins:

 the structure of DNA-dependent RNA polymerase is different in prokaryotes and eukaryotes;

 antimicrobial selectivity in rifamycins is moderate.

Spectrum of antimicrobial action of rifamycins:

 they are effective against M. tuberculosis, Staphylococcus spp.,

Streptococcus spp. (including S. pneumoniae), N. gonorrhoeae, N. meningitidis at

low concentrations;

 they are effective against E. coli, Proteus spp. at higher concentrations;

 they are effective against strains of microorganisms resistant to semi-

synthetic penicillins and cephalosporins.

Pharmacokinetics of rifampicin:

 The concentration in the blood is maximum in 30 minutes with intramuscular introduction; the therapeutic concentration maintaines for 6–8 hours. They stay in the foci of inflammation for a long time.

 Rifampicin is readily absorbed when ingested, simultaneous food intake reduces its bioavailability by about 30 %.

 They easily bind to plasma proteins.

 Heavy concentrations are observed in the liver, kidneys, lungs, ascitic and

pleural fluids, bones.

 They do not penetrate the intact blood-brain barrier but penetrate through the placental barrier.

 Most of the drug is excreted with bile, excretion through the kidneys is insignificant.

 Partial reabsorption occurs in the intestine, which causes prolonged circulation in the body. The plasma content increases at cholestasis.

Indications of rifamycins aministration:

 tuberculosis, leprosy;

 pneumonia caused by polyresistant strains of staphylococci;

 treatment of diseases caused by hemophilic bacillus, including pneumonia

and meningitis, eradication of hemophilic bacillus from nasopharynx;

 osteomyelitis;

 biliary tract infections.

Undesirable effects of rifamycins:

 hepatotoxic effect (hepatitis, hyperbilirubinemia, increased activity of hepatic transaminases);

 neurotoxic effect (headache, vision disorders, ataxia, disorientation);

 myopathy due to atrophy of muscle fibers (with prolonged use of the drug);

 allergic reactions;

 irritating effect, dyspeptic phenomena when taken orally; phlebitis when

introduced intravenously;

 urine, sputum, tears and contact lenses, feces and skin become of orange-red color.

Contraindications of rifamycins:

 Jaundice that is recently transferred (less than a year ago), infectious hepatitis;

 severe renal dysfunction;

 pregnancy, lactation;

 allergic reaction to rifamycins.

2.9. LIPOPEPTIDES

Lipopeptides are antibiotics with a lipopeptide structure, namely a lipoprotein of bacterial origin.

Lipoprotein is a chemical substance containing a lipid bound covalently to a protein or peptide.

Daptomycin, surfactin — lipopeptides used in medicine.

2.10. POLYMYXINS

Polymyxins are antibiotics having the structure of cyclic peptides with a narrow spectrum of antimicrobial action; they are effective only against gramnegative microorganisms.

Fusafungin (fig. 16) isolated from Fusarium lateritium fungi culture and gramicidin C produced by some Bacillus brevis strains are also cyclic peptides; their

pharmacodynamic and pharmacokinetic properties are similar to those of polymyxins; a wider spectrum of their antimicrobial action allows to treat them as a separate group.

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