ANTIBIOTICS

superbugs
microorganisms with multiply resistance

 MRSA - methicillin/oxacillin-resistant
Staphylococcus aureus
 VISA - vancomycin intermediate resistant
Staphylococcі
 VRE - vancomycin-resistant enterococci
 ESBLs - extended-spectrum beta-lactamases
(microorganisms – resistant to cephalosporins and
monobactams)
 PRSP - penicillin-resistant Streptococcus pneumoniae
1952 – 100 % Staphylococcus infections were cured by penicillin
1982 – only 10 % infections
At nowadays ?........
MRSA causes 19 000 deaths annually in USA (more than VIL)
 ANTIBIOTICS
 Beta-lactam antibiotics:
Penicillins
Cephalosporins
Monobactams
Carbapenems
 Macrolides, azalides.
 Fluoroquinolones
 Linkozamides.
 Tetracyclines.
 Aminoglycosides.
 Chloramphenicols.
 Glycopeptides.
 Cyclic polipeptides (polimixins).
 Nitroimidazoles.
 Beta-lactams
 bactericidic action (damage of cell walls) of bacteria, which
multiply;
 short half-life;
 Maximum plasma concentration - in the first hour after systemic
administration;
 output mostly by kidneys by tubular secretion and glomerular
filtration;
 synergism of action with aminoglycosides and glycopeptides;
 broad spectrum of antimicrobial activity;
 no effect on pathogens that persist intracellularly;
 non-toxic and have a wide range of therapeutic concentrations -
do not require therapeutic drug monitoring.
 Beta-lactams
 The incidence of allergic reactions:
 penicillins 5 - 10%
 cephalosporins 2%
 carbapenems and monobactam <1%
 Contraindicated only when documented hypersensitivity.
 If hypersensitivity to penicillin cross-hypersensitivity to
other beta-lactams - 10% (in the case of severe allergic
reactions their use is not permitted).
 The level of security when used in pregnant women - B
 PENICILLINS
 1 generation - natural (biosynthetic) penicillins:
 benzathine benzylpenicillin
 benzylpenicillin
 Phenoxymethylpenicillin
Semisynthetic penicillins:
 2 generation - antistaphylococci penicillinase resistant
penicillins – (izoxazolil-penicillins):
 Dykloksatsylin
 Kloksatsylin
 Methicillin (causing 2-10% of patients with interstitial nephritis)
 Naftsylin
 Oxacillin
 Flukloksatsylin
 PENICILLINS
 3 generation - penicillins with broad spectrum -
aminopenicillins;
 Ampicillin, Amoxicillin
 4 generation (antipseudomonade) - carboxypenicillins:
 carbenicillin
 ticarcillin
 5 generation (antipseudomonade) - ureido- and
piperazynopenicillins:
 azlocillin,
 piperacillin
 6 generation - amidynopenicillins:
 Amdinocillin
 inhibitors of beta-lactamases

Clavulanic acid,
sulbactam,
tazobactam
 “Inhibitor protected” penicillins :

 Amoxicillin / clavulanat:
Amoxiclav
Augmentin
Flemoclav
Klavocin
 Ampicillin / sulbactam:
Unazyn
Sultamicin
Ampisulbin
 Ticarcillin / clavulanat: Timentin
 Piperacillin / tazobactam, Tazocin
 Adverse effects (AE) of
biosynthetic penicillins

 Allergic reactions (10 %)

 Endotoxic shock
 Disorders of electrolyte balance
 Neurotoxic reactions (in using of big doses) –
encephalopathy (hyperreflexia, seizures,
hallucinations, coma)
 Interstitial nephritis
 Oxacillin

Antistaphylococci penicillinase-resistant
semisynthetic penicillin, acid stable

Administration: intramuscular, intravenously,

oraly 3-6-8 g/24 hours (4-6 times of injections)
 Differences between ampicillin and amoxicillin
Parameters Ampicillin Amoxycillin

Activity towdards
- pneumococci ++ +++
- H. pylori + +++
- salmonella ++/+++ +++
- shigella +++ +
Bioavailability after oral
administration 40 % 90 %
Influence of food on
bioavailability dicreases in 2 times no influence
Level in sputum low high
Level in urine high very high
Appearance of diarrhea frequently rarely
 Indications for administration of amoxicillin
Localisation of ifection Drug of choice Alternative drug

Respiratory tracts Acute midlle otitis Acute pharingitis

Bacterial sinusitit Chronical bronchitis
Acute bronchitits
Extrahospital
pneumonia of light or
medium-severe
complexity
Kidneys and urinary Acute pielonephritis Chronical pielonephritis
tracts Acute cystitis Acute prostatitis
Bacteriouria in children Gonorrhea
and pregnant women

Digestive tract Cholangitis, cholecystitis

Typhoid fever
Other pathology Borreliosis Leptospirosis
 Amoxicillin / clavulanat

Gram-positive and gram-

negative aerobes and
anaerobes
Unasyn (ampicillin/sulbactam)
 Side effects of semisynthetic
penicillins
 Irritation of mucous membrane of digestive tract
(diarrhea)
 Disbacteriosis
 Superinfection (colonizing of gut with Candida fungi,
enterococci, Pseudomonas aeruginosa, clostridia)
 Pain in injection area, aseptical inflammation,
phlebitis
 Allergic reactions
 Granulocytopenia (oxacillin)
 Reduction of platelets agregation (ampicillin)
 Disorders of liver function
 Encephalopathy (in introduction of high doses)
 Anti-pseudomonade PENICILLINS

 indication for use - mainly hospital infections caused by

susceptible microorganisms;
 not recommended as monotherapy;
 In infections caused by Pseudomonas aeruginosa and
mixed aerobic-anaerobic infections - combination with
aminoglycosides and fluoroquinolones;
 To be careful when hypernatremia, hypokalemia, bleeding
caused by dysfunction of erythrocyte membranes.
 Classification of cephalosporins

Way of Generation of cephalosporin antibiotics

introducti
on I II III IV V
Injection Cefaloridin Cefamandole Cefotaxime Cefpirom Ceftobi-
(IV/IM) Cefadroxil Cefoxytyn Ceftriaxone e prol
Cefazolin Cefuroxime Cefopera- Cefepime
Cefalexin zone
Cephradin Ceftazidime

Oral (PO) Cephalexin Cefuroxime Cefixime

Cefadroxil axetyl Cefpodoxi-me -
Cefaclor
First Generation:
The optimum activity is against gram-positive bacteria
such as staphylococci and streptococci, have little gram-
negative spectrum (Cefazolin, Cephalexin, Cefadroxil).

Second Generation:
Have more spectra against gram-negative bacteria
(Haemophilus influenzae, Enterobacter aerogenes) in
comparison to the first generation. Their gram positive
spectrum is less than the first generation (Cefaclor,
Cefuroxime, Cefuroxime axetyl - Zinnat).
Third Generation:
Broad spectrum, effective against both gram positive and
gram negative bacteria (Ceftriaxone, Cefoperazone,
Ceftazidime, Cefixime - Cefix, Cefpodoxime – Cefma,
Auropodox).

Fourth Generation:
Their spectra is comparable to 3rd generation, show more
resistance to betalectamases (Cefipime, Cefpirome,
Cefozelis).

Fifth Generation:
Extended spectrum. Pneumonia, skin and soft tissue
infections. MRSA. (Ceftaroline, Ceftobiprol)
Cefalexin ( C I)
Zinnat (Cefuroxime, C II)
Cefotaxime (C III)
Claphoran (cefotaxime, C III)
Cefobid (Cefoperazone, C III)
Зефтера (Ceftobiprole
medocaril)
 Antimicrobial spectrum of cephalosporins
Generation of Active towards Stability towards beta-
cephalosporins lactamase
Gram- Gram- Staphylo Gram-
positive negative cocci negative
bacteria bacteria bacteria
І +++ +/- ++ -

ІІ ++ + ++ +/-

ІІІ + +++ + +
ІV ++ +++ ++ ++
 AE of cephalosporins
 Irritation of mucous membrane of digestive tract,
infiltrates after intromuscular introduction , phlebitis
after inrtavenous introduction
 Disbacteriosis, superinfection
 Allergic reactions, including cross allergy with
penicillins
 Granulocytopenia (in case of treatment during more
than 2 weeks)
 Hemorrhages (inhibition of synthesis of factors of
blood coagulation in liver) – cephalosporins ІІІ
 Nephrotoxicity (accumulation in epithilial cells of
kidney canalicules)
 Encephalopathy (hyperreflexia, seizures, coma)
 “Inhibitor protected” cephalosporins

 Ceftriaxone+sulbactam (Sulbactomax)
 Cefoperazone+sulbactam (Sulperazon)
 Ceftazidime+sulbactam (Norzidim)
 Cefepime+sulbactam (Norfepim)
 Cephalosporines

Not recommended
to combine with other nephrotoxic drugs
(aminoglycosides)

Contraindicated
to combine with loop diuretics (furosemid,
etacrinic acid)
Antipseudomonade cephalosporines

Cefoperazone
Ceftazidime

Cefepime
Cefpirome
 Monobactams
Aztreonam

Action spectrum - Gram (-) bacteria, including

Escherichia coli, Clebsiellas, Proteus, Haemophilus
influenzae (activity is equal to the activity of cephaloporins
of third generation)
Ways of introduction: oral (20% are being absorbed),
intramuscular, intravenous
Clinical use: sepsis, infection of urinary tract, soft
tissues, meningitis and others (often combined with
aminoglycosides , clindamycin, metronidazole,
vankomycin).
Carbapenems (tienamytsin)

Tienam (imipenem + cylastatin)

Meropenem

The widest spectrum of antibacterial action

most of aerobe and anaerobe Gram (+) and
Gram (-) bacteria, including those which
produce beta-lactamase
 Classificaion of macrolides

І. Natural: erythromycin,
oleandomycin, spiramycin,
jozamycin, midecamycin.
ІІ. Semi-synthetic: roxythromycin,
clarithromycin, flurythromycin,
dyrythromycin, miokamycin,
rokitamycin.
III. Azalides (neutrogen atom is
introduced in lacton ring):
azithromycin.
Macropen (midecamycin)
Sumamed (azithromycin)
 Spectrum of action of maclrolides
and azalides
 staphylo-, strepto-, hono-, anaerobe cocci,
enterobacteria
 H.influenzae (clarythromycin, azithromycin)
 intracellular situated microorganisms (strains
of Helicobacter, Chlamydia, Legionellа,
M. pneumoniae, U. urealyticum etc.)
 Pharmacokinetics of
macrolides
Quiclkly and fully distributed through the
tissues (do not pass through HEB)
Correlation of tissues/blood concentration :
 Erythromycin – (5-10) : 1
 Azithromycin – (100-500) : 1
 Their concentration in phagocyting cells
prevails concentration in blood pasma in 12-
20 times, they get accumulated in source of
inflammation - macrolides paradoxis
Indications for usage of macrolides and
azalides

ENT- infections, infections of upper

respiratory tracts, gynecological infections,
skin and soft tissues infections; ulcer
disease; dyphteria; whooping-cough;
honorrhea; syphilis; typhoid fever
(azithromycin).
First line drugs for: mycoplasma, chlamidia,
legionella pneumonia
 AE of macrolides
 Dispeptic disorders, disbacteriosis, superinfection
 Cholestasis, cholestatic jaundice (erythromycin)
 Depression of liver microsome enzyme activity
(erythromycin, oleandomycin can not be
combined with theophylline, ergot alkaloids,
carbamazepine)
 Development of resistance in process of treatment
 Fluoroquinolones
 Very broad-spectrum antibiotic.
 Kill rather than inhibit.
 Cipro is most active against aerobic gram
- organisms.
 Not indicated for children under 18 or
pregnant women.
 Adverse effects: arthropathy, GI upset.
AE of Quinolones
 Linkosamides
Linkomycin Clindamycin

 spectrum: Gram positive aerobe cocci,

grampositive and gramnegatvie anaerobes
 Penetrate all the tissues (don’t pass through
HEB) including intracellurally
 Usage: usually in severe infections, caused by
anaerobe microorganisms
 A lot of side effects
 Linkomycini
hydrochloridum
Dalacyn C (clindamycini
hydrochloridum)
 Tetracyclines

1. Natural - biosynthetic:
chlortetracycline, oxytetracycline,
tetracycline,
dimethylchlortetracycline.
2. Semisynthetic:
doxycycline (vibramycin), metacycline
(rondomycin), minocycline.
 tetracyclines administration

 Tetracycline - 0,25-0,5 g 4 times per 24

hours
 Methacycline – 0,3-0,6 g 2 times per 24
hours
 Doxycycline – 0,2 g (first day), 0,1g (next
days) 1 time per 24 hours
Pharmacokinetics of tetracyclines when combined with
other drugs

Drugs Results of combined administration

Antacides (Ca+, Mg+ Decrease of absorbtion

etc.)

Iron preparations Decrease of absorbtion

Rifampicin Increase of elimination

 Side effects of tetracyclines
 Dispeptic disorders, stomatitis, glositis,esophagitis,
pruritus etc).
 Disbacteriosis and superinfection with Candida fungi,
proteus, pseudomonadas or staphylococci.
 Photodermatosis.
 Liver toxicity.
 Absorbtion by bones and teeth of a featus or a child:
hipoplasia of dental enamel, disorder of teeth
formation, tendency for caries.
 Antianabolic action, damage of kidneys (when using
tetracyclines with long termed storage, using big
doses).
Tetracyclines are forbidden for children under the age of
8/12, during pregnancy, liver diseases, kidney
insufficiency, miastenia
Photosensitization - tetracyclines
tetracyclines
 AMINOGLYCOSIDES
 І generation: streptomycin,
neomycin, monomycin, kanamycin

 ІІ generation: gentamycin
(garamycin), tobramycin, syzomycin

 ІІІ generation: netilmycin

(netromycin), amikacin.
 Spectrum of aminoglycosides action
wide
 gram-negative bacteria (escherichia coli,
salmonella, klebsiella, especially K.
рneumoniae, proteus, iersinia, brucella,
campilobacteria, helicobacters, serratsia,
shigella etc.).
 some gram-positive microorganisms,
including staphylococci which are resistant
to other antibiotics
 Indications for aminoglycosides
- at the beginning stage of infectious processes of unknown
ethiology and severe complexity (combined with beta-
lactamase);
- considerable purulent-inflammatory component of severe
infections (peritonitis, sepsis, mediastinitis, abscesses and
flegmones of soft tissues);
- acute attack of chronical purulent-inflammatory diseases,
including secondary immune defficiency;
- early stage of development of secondary bacterial
meningitis;
- bacterial endocarditis;
- infections of urinary tracts;
- for prevention of postoperative pustural complications
(combined with beta-lactamase antibiotics, metronidazole
or other antianaerobe drugs);
- skin infections and subcutaneous fat tissue infections, burns.
Concentration of aminoglycosides in
blood should not overcome:

 Amikacin, kanamycin –
35-40 mkg/ml
 Gentamicin, tobramycin –
10-12 mkg/ml
AE in administration of aminoglycosides

 Ototoxicity
 Nephrotoxicity
 Neurotoxicity
According to extent of toxicity
netilmicin < gentamicin <tobramycin <
amikacin < neomycin < streptomycin <
monomycin < kanamycin

 Leuko-, thrombocytopenia, hemmorhages,

hemolisis
 Allergic reactions
 Chloramphenicol –
levomycetin

Indications:
meningitis, typhoid fever, paratyphoid fever,
brucellosis, tularemia

Side effects:
 Hypochrome and aplastic anemia
 Granulocytopenia, thrombocytopenia
 «Grey syndrome of a featus»
 Disbacteriosis and superinfection
Glycopeptide antibiotics
Vankomycin, Teikoplanin

 Active towards МRS і MRCNS

 First line medicine for
Clostridium defficile - associated colitis
 Nitro-imidazoles
• Tinidazole;
• Metronidazole;
• Ornidazole.
Indications for metronidazole
AE of nitroimidazoles
 Antimicrobial therapy in respiratory infections caused by
Pseudomonas aeruginosа
 Cephalosporines (CPS) III gen.:
Ceftazidime, Cefoperazone, Cefoperazone / Sulbactam
 Cephalosporines IV Gen.:
Cefepime, Cefpirome
 Protected ureidopenicillines:
CPS III-IV gen.
Piperacillin / tazobactam +
 Protected karboxypenicillines: AG or FH
Ticarcillin / clavulanate
 Monobactams (MB):
Aztreonam
FH or CP
 Carbapenems (CP):
Imipenem, Meropenem, Ertapenem
+
 Fluoroquinolones (FH): AG or MB
Ciprofloxacin, Levofloxacin
 Aminoglycosides (AG):
Tobramycin, amikacin
 Oxazolidinones: Lіnezolіd (Zivox)

 synthetic drugs, active against a large spectrum

of multiresistant Gram + bacteria, including
methicillin- and vancomycin-resistant
staphylococci, vancomycin-resistant
enterococci, penicillin-resistant pneumococci
and anaerobes.
 Less effective (not effective) against Gram –
bacteria
 accumulation in the bone and lung tissue,
vegetations, haematoma, cerebrospinal fluid
(pneumonia, skin, soft-tissue infections…)
 Cyclic lipopeptides: Daptomycin
(Cubicin)
 Natural, active against multiresistant gram-positive
pathogens, particularly staphylococci, only IV 4 mg/kg (6
mg/kg) 1 р/д.
 Do not use for Pneumonia. Poorly penetrates lung.
Inactivated by surfactant