Добавил:
ivanov666
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Antibiotics. Study aid
.pdf
11
Selectivity of antimicrobial action of β‑lactam antibiotics:
no cell wall in animals and humans; acetylmuramic acid is not a metabolite;
penicillin-binding proteins do not function;
β‑lactam antibiotics have a high selectivity of antimicrobial action.
Undesirable effects of β-lactam antibiotics:
allergic reactions — urticaria, fever, bronchospasm, vasculitis, serum
sickness, Quincke's edema, erythroderma, Stevens-Johnson syndrome, eosinophilia.
Anaphylactic shock with 10% mortality is the most dangerous (penicillins). Crossallergy is possible between β-lactam antibiotics;
neurotoxicity due to antagonism with GABA — tremor, convulsive
syndrome, hallucinations. The condition is more often while taking benzylpenicillin
and ampicillin, less often is noted when imipenem is administered;
endotoxic shock;
dysbacteriosis (more often candidiasis of the oral cavity, vagina, intestines
when using drugs whose spectrum of action includes gram-negative flora);
irritating effect — soreness and infiltration with intramuscular
administration, phlebitis with intravenous administration.
2.1.1. Penicillins
Penicillins are antibiotics that are derivatives of 6‑aminopenicillanic acid.
Classification of penicillins by origin:
biosynthetic;
semi-synthetic.
Classification of biosynthetic penicillins by route of administration and
duration of action:
1. Acid-resistant (administered orally) — phenoxymethylpenicillin.
2. Acid-resistant (administered parenterally):
of short action (3-4 hours) — benzylpenicillin sodium salt; benzylpenicillin
potassium salt;
medium duration (up to 9 hours) — benzylpenicillin novocaine salt;
prolonged action (more than a day) — bicillin‑1; bicillin‑5.
12
Pharmacokinetics of biosynthetic penicillins are destroyed by
penicillinases;
are destroyed by penicillinases;
are destroyed by hydrochloric acid; therefore, are not used inside;
phenoxymethylpenicillin is not destroyed by hydrochloric acid of the
stomach, it is prescribed orally; it is used in outpatient practice in the treatment of
lung infections of the upper respiratory tract (tonsillitis, pharyngitis), oral cavity,
uncomplicated pneumococcal pneumonia. NB! Absorption is limited and does not
guarantee achieving bactericidal concentrations in the focus of the infection.
duration of action of biosynthetic penicillins — see classification.
Spectrum of antimicrobial action of biosynthetic penicillins:
gram-positive cocci: streptococci, pneumococci, enterococci (resistant to
low concentrations), staphylococci (most strains of S. aureus and S. epidermidis are
resistant because they produce β-lactamases);
gram-negative cocci: meningococci, gonococci (in most cases capable of
producing β-lactamase);
gram-positive rods: listeria, pathogens of diphtheria, anthrax;
spirochete: pale treponema, leptospira, borrelia;
anaerobes: spore-forming — clostridia; non-spore-forming — peptococci,
peptostreptococci, fusobacteria (the main representative of non-spore-forming
intestinal anaerobes B. fragilis is resistant);
actinomycetes.
Indications to administer biosynthetic penicillins:
streptococcal and pneumococcal infections — tonsillopharyngitis,
erysipelas, scarlet fever, pneumococcal pneumonia;
leptospirosis, borreliosis (Lyme disease);
Anthrax;
Actinomycosis;
meningococcal meningitis, infectious myocarditis, clostridial gas gangrene,
tetanus, aspiration pneumonia (high doses of benzylpenicillin sodium salt);
secondary prevention of rheumatism and treatment of advanced syphilis
(prolonged (durant) drugs).
Classification of semi-synthetic penicillins by chemical structure:
Isoxazolpenicillins — oxacillin, cloxacillin, flucloxacillin;
13
Aminopenicillins — ampicillin, amoxicillin;
Amidinopenicillins — mecillinam, amdinocillin, pivamdinocillin;
Carboxypenicillins — carbenicillin, carfecillin, ticarcillin;
Ureidopenicillins — azlocillin, meslocillin, piperacillin.
Isoxazolpenicillins
Inferior to biosynthetic penicillins and aminopenicillins in antimicrobial
activity.
Being not destroyed by staphylococcal-lactamases and able of blocking their
activity, they are the drugs of choice in the treatment of staphylococcal infection (skin
and soft tissues, bones and joints, endocarditis and brain abscess).
Ampiox (oxamp) — such a combination of ampicillin and oxacillin is
administered in the empirical therapy of staphylococcal infections.
Aminopenicillins
They act on both gram-positive microorganisms such as S. pyogenes,
S. pneumoniae, B. pertussis, C. diphtheria, L. monocytogenes, H. pylori,
M. catarrhalis, S. aureus and gram-negative microorganisms E. coli,
R. mirabilis, salmonella, shigella (the latter are often resistant), H. influenza as well
as on some anaerobes that do not form β -lactamases.
Their action on enterococci and listeria is more active than that of
benzylpenicillin.
The action on streptococci, staphylococci, spirochetes and anaerobes is
weaker than that of biosynthetic penicillins.
They are destroyed by β -lactamases of staphylococci (MRSA) and gram-
negative bacteria.
They produce no effect against gram-negative pathogens of nosocomial
infections such as Pseudomonas aeruginosa, Klebsiella, serratia, etc.
Features of several aminopenicillins:
amoxicillin — taken orally has a bioavailability of 80-90%, creates high and
stable concentrations in blood and tissues;
amoxicillin is used as starting therapy of mild infections of the ENT organs
(sinusitis, otitis media), lower respiratory tract (acute bacterial bronchitis,
14
community-acquired bacterial pneumonia), urinary tract (acute cystitis, acute
pyelonephritis, asymptomatic bacteriuria), some intestinal infections (typhoid fever);
ampicillin is more often used parenterally and in combination with
aminoglycosides to treat community-acquired infections (endocarditis, meningitis,
listeriosis of newborns). It is efficient against enterococci (especially St. faecum). It is
administered to treat bacterial dysentery.
Amidinopenicillins
The spectrum of action includes only gram-negative enterobacteria —
Escherichia, shigella, salmonella, klebsiella, proteus.
The bioavailability is about 40% with the enteral route of administration.
They are prodrugs metabolized to form an active metabolite in the intestinal
wall; being inactive in the intestinal lumen they do not cause dysbiosis.
Carboxypenicillins and ureidopenicillins
The spectrum of action is wide, the activity against P. aeruginosa is of the
greatest importance though many of its strains are resistant today. The effect on
Pseudomonas aeruginosa is arranged in the following order: azlocillin = piperacillin
> meslocillin = ticarcillin > carbenicillin. Due to the rapid development of resistance
in pseudomonas infection, they are used only in combination with aminoglycosides
of II-III generations or fluoroquinolones.
Staphylococci are outside the spectrum of action of carboxypenicillins.
The spectrum of action of ureidopenicillins additionally includes klebsiella,
serration, E. coli, Enterobacter.
Main indications: severe hospital infections of various localization
(respiratory tract, urinary tract, intraabdominal or gynecological infections) caused by
sensitive microorganisms, especially Pseudomonas aeruginosa; the presence of
mixed aerobic-anaerobic infection.
“Protected” penicillins
“Protected” penicillins are combined preparations containing β-lactams and
β-lactamase inhibitors.
15
Examples of drugs:
amoxicillin /clavulanic acid (amoxiclav, augmentin);
ticarcillin/clavulanic acid (thimentin);
ampicillin /sulbactam (unazine, sulacillin);
piperacillin /tazobactam (tazocin).
Amoxicillin (fig. 2) + clavulanic acid (fig. 3) = Amoxiclav.
Fig. 2. Structure оf amoxicillin
Fig. 3. Structure оf clavulanic acid
Spectrum of antimicrobial action of “protected” penicillins:
gram-positive cocci: staphylococci (including penicillin-resistant strains of
S. aureus and S. epidermidis), streptococci, enterococci;
gram-negative rods: H. influenzae, M. catarrhalis, N. gonorrhoeae, E. coli,
Proteus spp., Klebsiella including β-lactamase-producing strains;
anaerobes: both spore-forming and non-spore-forming, including B. fragilis.
Indications to administer “protected” penicillins:
bacterial infections of the upper and lower respiratory tract;
biliary tract infections (acute cholecystitis, cholangitis);
urinary tract infections (acute pyelonephritis, cystitis);
intraabdominal and pelvic infections;
infections of skin and soft tissues (including wound infections after bites),
bones and joints;
neutropenic fever (in combination with ciprofloxacin);
sepsis;
meningitis caused by H-lactamase-producing strains of H. influenzae;
perioperative antibiotic prophylaxis.
16
Undesirable effects and contraindications of penicillins
Undesirable effects common to all β-lactam antibiotics:
hyperkalemia while using benzylpenicillin potassium salt;
hypernatremia while using benzylpenicillin sodium salt.
Contraindications:
allergic reaction to penicillins or other lactam antibiotics in the anamnesis;
allergic reaction to procaine or lidocaine in the composition of durant
penicillin drugs; allergic reaction to using their solutions to dilute penicillin
medications.
2.1.2. Cephalosporins
Cephalosporins are antibiotics, derivatives of 7‑aminocephalosporanic acid
(fig. 4).
Fig. 4. Structure оf cephalosporins
Classification of cephalosporins by antimicrobial spectrum
and route of administration
Generations
Parenteral administration
Enteral administration
I generation
cephaloridin, cephalotin,
cefazolin
cephalexin, cefadroxil
II generation
cefuroxime, cefamandol,
cefoxitin
cefuroxime-axetil, cefaclor
III generation
cefotaxime, ceftazidime,
ceftriaxone, cefoperazone
ceftibutene, cefixime
IV generation
cefepim, cefpir, cefclidine
–
17
Cephalosporins of the first generation:
The spectrum of antimicrobial action includes gram-positive bacteria and
cocci except enterococci and MRSA.
Gram-negative bacteria have significantly less sensitivity.
Resistance to β -lactamases of staphylococci is low.
Are the drugs of choice against:
– tonsillopharyngitis;
– mild infections of skin and soft tissues.
Cephalosporins of the second generation:
Remain active against gram-positive microbes.
The spectrum additionally includes gram-negative bacteria H. influenzae,
M. catarrhalis, E. coli, R. mirabilis, P. vulgaris.
They have higher resistance against β-lactamases of gram-negative bacteria
than cephalosporins of the first generation.
Pseudomonas aeruginosa, enterococci, anaerobes are resistant.
They are drugs of choice against:
– respiratory tract infections (chronic bronchitis, community-acquired
pneumonia), acute otitis and sinusitis;
– urinary tract infections (pyelonephritis, cystitis);
– infections of skin and soft tissues.
Third generation of cephalosporins:
They are highly active to gram-negative flora including problematic
microorganisms such as serrations, citrobacteria, indole-positive proteas due to their
high resistance to various β-lactamases.
They are much less active against gram-positive strains, especially
staphylococci than drugs of the I and II generations.
They are indicated in treatment of severe, including nosocomial, infections
of various localization, meningitis and acute gonorrhea.
Only ceftazidime and cefoperazone suppress Pseudomonas aeruginosa.
Only cefotaxime is active against anaerobes.
Ceftriaxone, cefotaxime, ceftazidime easily penetrating the blood-brain
barrier are recommended to treat bacterial meningitis.
Ceftriaxone with the longest duration is administered once a day.
18
Fourth generation of cephalosporins:
They have a very broad spectrum of action. They are equally active to both
gram-negative and gram-positive flora.
They affect multi-resistant microorganisms with resistance to the extended
spectrum of β-lactamases.
Bacteroids are outside the spectrum of action; therefore a combination with
carboxy- and ureidopenicillins, metronidazole, etc. is possible. They are combined
with aminoglycosides, monobactams, carboxy- and ureidopenicillins to enhance the
effect on pseudomonads.
They easily penetrate all barriers and the cell membrane, create high
concentrations in the periplasmic space of microorganisms.
They are administered only parenterally.
They are used for severe, mainly nosocomial, infections caused by
polyresistant microflora: pneumonia, lung abscess, pleural empyema, intraabdomial
infections, sepsis. They are administered to treat infections against the background of
neutropenia and other immunodeficiency conditions.
Undesirable effects and contraindications of cephalosporins
Undesirable effects common to all β-lactam antibiotics:
nephrotoxicity — in cephalosporins of I–II generations;
hepatotoxicity — in cephalosporins of II–III generations;
disorders of blood clotting as a result of antagonism with vitamin K — in
cephalosporins of II-III generations.
Cefamandol and cefoperazone inhibit acetaldehyde oxidase; therefore, alcohol
and alcohol-containing drugs are prohibited with their intake to avoid disulfiram-like
reactions.
Contraindications:
allergic reaction to cephalosporins or other β-lactam antibiotics in the
anamnesis;
allergic reaction to procaine or lidocaine when using their solutions to dilute
cephalosporin medications.
19
2.1.3. Carbapenems
Carbapenems are antibiotics with a β-lactam ring inside a complex
carbapenem ring.
Classification of carbapenems
At first only imipenem was used; then close to it meropenem and doripenem
appeared. The classification of carbapenems was irrational at that time. Nowadays
there is still no taxonomy among a significant number of new drugs.
It is possible to classify them according to the spectrum and the duration of
antimicrobial action:
I generation — imipenem, meropenem, doripenem;
II generation — ertapenem;
III generation — CS-023 and other drugs under development.
Carbapenems of the first generation:
The spectrum of action is broad enough including P. aeruginosa though
excluding MRSA and Enterococcus faecium.
Frequency of administration — at least 2-3 times a day.
Indications for use — nosocomial infections (pneumonia, lung abscess,
pleural empyema, intraabdominal infections, sepsis, bone and joint infections,
endocarditis, meningitis, pelvic organ infections) as reserve drugs only in case the
antibiotics of choice are ineffective. The administration of carbapenems is especially
efficient in patients with weakened immunity (patients with neutropenia, cancer
patients).
Renal dipeptidase rapidly destroys imipenem; therefore, it is used only with
its inhibitor, namely cilastatin.
Carbapenems of the second generation:
The frequency of administration is once a day.
The spectrum of antimicrobial action is narrower than that of carbapenems
of the first generation (they do not act on all enterococci and non-fermenting gramnegative bacteria including P. aeruginosa).
Indications for use — severe and moderate community-acquired infections
as a reserve drug.
20
Carbapenems of the third generation: the spectrum of antimicrobial activity
includes MRSA.
Undesirable effects and contraindications of carbapenems
Undesirable effects common to all β-lactam antibiotics: imipenem may cause
the development of neutropenia (rarely agranulocytosis) due to the toxic effect on
granulocytopoiesis being used for more than 2 weeks.
Contraindications:
meningitis and traumatic brain injury;
allergic reaction to carbapenems;
I trimester of pregnancy.
2.1.4. Monobactams
Monobactams are antibiotics with an isolated β-lactam ring in their structure
(fig. 5).
Fig. 5. Structure оf monobactams
Only one synthetic drug, aztreonam, belongs to this group today.
Spectrum of antimicrobial action of aztreonam
It is resistant to many β-lactamases produced by aerobic gram-negative flora
but is destroyed by β-lactamases of staphylococci and bacteroids.
The activity of aztreonam against many representatives of the
Enterobacteriaceae family (E. coli, Enterobacter, Klebsiella, proteus, serratia,
Citrobacter, providences, morganella) and P. aegidinosa, including nosocomial
strains resistant to aminoglycosides, ureidopenicillins and cephalosporins is of
clinical significance.
It does not affect Acinetobacter spp., S. maltophilia, B. cepacia, gram-
positive cocci and anaerobes.
Соседние файлы в предмете [НЕСОРТИРОВАННОЕ]