antibiotics lector prof. posokhova k.a.. the problem drug companies have little interest in...
TRANSCRIPT
The problemThe problem
drug companies have little interest in financing the testing of their newly discovered antibiotics, because they are more focused on drugs that people require daily for the rest of their lives
superbugs superbugs microorganisms with multiply resistancemicroorganisms with multiply resistance
MRSAMRSA - methicillin/oxacillin-resistant methicillin/oxacillin-resistant Staphylococcus aureusStaphylococcus aureus
VISAVISA - - vancomycin intermediate resistant vancomycin intermediate resistant StaphylococcStaphylococcіі
VREVRE - vancomycin-resistant enterococcivancomycin-resistant enterococci ESBLsESBLs - extended-spectrum beta-lactamasesextended-spectrum beta-lactamases
(microorganisms (microorganisms – resistant to cephalosporins and – resistant to cephalosporins and monobactamsmonobactams))
PRSPPRSP - penicillin-resistant Streptococcus pneumoniaepenicillin-resistant Streptococcus pneumoniae
1952 – 100 % StaphylococcusStaphylococcus infections were cured by penicillin
1982 – only 10 % infections At nowadays ?........
MRSA causes 1MRSA causes 19 9 000 deaths000 deaths annually in USAannually in USA ( (more than VILmore than VIL))
Principles of rational antibiotic therapy
Presence of substantiated indications for Presence of substantiated indications for prescription of an antibioticprescription of an antibiotic
Choosing of the most effective and the least toxic Choosing of the most effective and the least toxic drug, indrug, in time administrationtime administration
Introduction of optimal doses with optimal Introduction of optimal doses with optimal frequency, taking into consideration complexity of frequency, taking into consideration complexity of the diseasethe disease
Choosing of the optimal way of introductionChoosing of the optimal way of introduction Estimation of duration Estimation of duration of of treatmenttreatment Control after treatmentControl after treatment Monitoring and prophMonitoring and prophyylalaxixis of negative side effectss of negative side effects Decision on expediency of combined antibiotic Decision on expediency of combined antibiotic
therapytherapy
ANTIBIOTICS Beta-lactam antibiotics:Beta-lactam antibiotics: А. Penicillins Б. Inhibitors of beta-lactamases and combined drugs, В. Cephalosporins Г. Monobactams Д. Tienamycin (carbapenems). Macrolides, azalides, streptogramins, prystinamycines. Linkozamides. Tetracyclines. Aminoglycosides. Chloramphenicols. Glycopeptides. Cyclic polipeptides (polimixins). Other antibiotics
ANTIBIOTICS
Dose-dependent Time-dependent
Antibacterial effect directly depends on their concentrations in the locus of inflammation
(high doses 1-2 times/24h)
Aminoglycosides Aminoglycosides
FFluluororoqoqinolonesinolones
MetronidazolMetronidazol
AmphoterAmphoteriicin Bcin B
Effectiveness depends on a period of time, during which concentration in blood overwhelms MIC for a particular causative agent
(constant i.v. infusion or 3-6 times/24h)
Beta-lactamesBeta-lactames
GlycopeptidesGlycopeptides
MacrolidesMacrolides
LinkozamidesLinkozamides
PENICILLINS PENICILLINS Natural (biosynthetic) penicillins:
benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), novocain salt of benzylpenicillin (benzylpenicillin procain), bicillin-1 (benzatyn benzylpenicillin), bicillin-3, bicillin-5.
Semisynthetic penicillins: 1 antistaphylococci penicillinase resistant penicillins –
izoxazolil-penicillins (oxacillin, dicloxacillin, methicillin); 2 of a spread spectrum – aminopenicillins (ampicillin,
amoxicillin); 3 antipseudomonade – carboxypenicillins (carbenicillin,
ticarcillin); ureidopenicillins (azlocillin, piperacillin, sulbenicillin); 4 combined with inhibitors of beta-lactamases -
“protected” penicillins (amoxicillin/clavulanate, ampicillin/sulbactam, ticarcillin/clavulanate, piperacillin/tazobactam).
Mechanism of penicillins actionMechanism of penicillins action
They form complexes with enzymes - trans- and carboxypeptidases (PCP), which control synthesis of peptidoglycan – component of cell-wall of microorganisms
Spectrum of action of biosynthetic penicllins
Gram-positive microorganisms
Gram-negative microorganisms
Streptococci
Bacillus anthracis
Causative agents of tetanus, gas gangrene
Actinomycets
Listeria
Gonococci
Meningococci
Moraxella
Causative agent of syphilis
Leptospiras
schemes on introduction oschemes on introduction off biosynthetic penicillins biosynthetic penicillins
Antibiotic, way of introduciton
One time dose Frequency of introduction
Benzylpenicillini sodium salt, i.m., i.v.
0,5-2 mln U (till 10 mln)
Every 4-6 hours (every
6 hours)
Benzatyn benzylpenicillin (bicillin-1), i.m.
0,3-0,6 mln U
1,2 mln U
1 time/week
1 time/2 weeks
Bicillin-3, i.m. 0,6 mln U 1 time/weekBicillin-5, i.m. 1,5 mln U 1 time/week
Complications of biosynthetic Complications of biosynthetic penicillinspenicillins
Allergic reactionsAllergic reactions (10 (10 %)%) Endotoxic shockEndotoxic shock Disorders of electrolyte balanceDisorders of electrolyte balance Neurotoxic reactionsNeurotoxic reactions ( (in using of big dosesin using of big doses) – ) –
encephalopathyencephalopathy ( (hyperreflexiahyperreflexia, , seizuresseizures, , hallucinationshallucinations, , comacoma))
Daily dose of BPDaily dose of BP during intratecal during intratecal introductionintroduction should not overcomeshould not overcome 10 10 000 000 UU
(5(5 000 000 UU – – for childrenfor children)) Interstitial nephritisInterstitial nephritis
OxacillinOxacillin
Antistaphylococci penicillinase-resistant semisynthetic penicillin, acid stable
Administration: intramuscular, intravenously, oraly 3-6-8 g/24 hours (4-6 times of injections)
.
Spectrum of action of aminopecillins (ampicillin, amoxicillin)
wide spectrum, destroyed by beta-lactamases
Influence on: streptococci, Haemophilus influenzae, causative agent of wooping cough, gonococci, meningococci, proteus,
Escherichia coli, salmonella, shigella
Differences between ampicillin and amoxicillin Differences between ampicillin and amoxicillin
Parameters
Ampicillin Amoxycillin
Activity towdards
- pneumococci
- H. pylori
- salmonella
- shigella
Bioavailability after oral administration
Influence of food on bioavailability
Level in sputum
Level in urine
Appearance of diarrhea
++
+
++/+++
+++
40 %
dicreases in 2 times
low
high
frequently
+++
+++
+++
+
90 %
no influence
high
very high
rarely
Indications for administration of amoxicillin Localisation of ifection Drug of choice Alternative drug
Respiratory tracts Acute midlle otitis
Bacterial sinusitit
Acute bronchitits
Extrahospital pneumonia of light or medium-severe complexity
Acute pharingitis
Chronical bronchitis
Kidneys and urinary tracts
Acute pielonephritis
Acute cystitis
Bacteriouria in children and pregnant women
Chronical pielonephritis
Acute prostatitis
Gonorrhea
Digestive tract Cholangitis, cholecystitis
Typhoid fever
Other pathology Borreliosis Leptospirosis
SSide effects of ide effects of semisemisynthetic synthetic penicillinspenicillins
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)
Inhibitor-protected (“screened”, “protected”) Inhibitor-protected (“screened”, “protected”) penicillinspenicillins
Amoxicillin/clavulanateAmoxicillin/clavulanate (amoxyclav, augmentin)(amoxyclav, augmentin)
AmpicillinAmpicillin/sulbactam/sulbactam (sultamycillin, unasin)(sultamycillin, unasin) TicarcillinTicarcillin/clavulanate/clavulanate
(timentin)(timentin) PiperacillinPiperacillin/tazobactam/tazobactam
Structure of cephalosporinsL – beta-lactame ring, D – dihydrothiazine ring
CH2 O CO CH3
C
O
H2N
O
OH
S
L D
N
Classification of cephalosporinsClassification of cephalosporins
Way of introduction
Generation of cephalosporin antibioticsGeneration of cephalosporin antibiotics
ffirstirst I I secondsecond II II thirdthird III III fourthfourth IV IV
Injection CefaloridinCefaloridin
Cefadroxil*Cefadroxil*
Cefazolin*Cefazolin*
Cefalexin*Cefalexin*
Cephradin*Cephradin*
Cefamandole* Cefamandole* Cefoxytyn*Cefoxytyn*
Cefuroxime*Cefuroxime*
Cefotaxime*Cefotaxime*
Ceftriaxone*Ceftriaxone*
Cefoperazone*Cefoperazone*
Ceftazidime*Ceftazidime*
Cefpirome*Cefpirome*
Cefepime*Cefepime*
Oral Cephalexin *Cephalexin *
Cefadroxil*Cefadroxil*
Cefuroxime Cefuroxime axetyl axetyl* *
Cefaclor *Cefaclor *
Cefixime *Cefixime *
Ceftibuten *Ceftibuten * --
Antimicrobial spectrum of cephalosporins
Generation of cephalosporins
Active towards Stability towards beta-lactamase
Gram-positive bacteria
Gram-negative bacteria
Staphylo cocci
Gram-negative bacteria
ІІ ++++++ +/-+/- ++++ --
ІІІІ ++++ ++ ++++ +/-+/-
ІІІІІІ ++ ++++++ ++ ++
ІІVV ++++ ++++++ ++++ ++++
Complications, caused by 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)
Cephalosporines Cephalosporines
NNot recommendedot recommended to combine with other nephrotoxic drugs
(aminoglycosides)
ContraindicatedContraindicated to combine with loop diuretics (furosemid,
etacrinic acid)
MonobactamsMonobactamsAztreonam
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 uses: sepsis, infection of urinary tract, soft tissues, meningitis and others (often combined with aminoglycosides , clindamycin, metronidazole, vankomycin).
Carbapenems (tienamytsin)Carbapenems (tienamytsin)
Tienam (imipenem + cylastatin) Tienam (imipenem + cylastatin)
MeropenemMeropenem
The widest spectrum of antibacterial action most of aerobe and anaerobe Gram (+) and Gram (-) bacteria, including those which produce beta-lactamase
Classificaion ofClassificaion of macrolidesmacrolides
І. Natural substances: erythromycin, І. Natural substances: erythromycin, oleandomycin,oleandomycin, spiramycin, spiramycin, jozamycin, midecamycin.jozamycin, midecamycin.
ІІ. ІІ. SemiSemi-synthetic substances: -synthetic substances: roroxxythromycin, clarithromycin, ythromycin, clarithromycin, flurythromycin, dyrythromycin, flurythromycin, dyrythromycin, miokamycin, rokitamycin.miokamycin, rokitamycin.
IIIIII. Azalides. Azalides (neutrogen atom is (neutrogen atom is introduced in lacton ring): introduced in lacton ring): azithromycin.azithromycin.
spectrum spectrum of aof action of maclrolides ction of maclrolides and azalidesand 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 Pharmacokinetics of macrolidesmacrolides
Quiclkly and fully distributed through the tissues (do not pass through HEB)
Correlation Correlation concentration concentration tissues/blood:tissues/blood:Erythromycin – (5-10) : 1Azithromycin – (100-500) : 1Their 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 Indications for usage of macrolides and azalidesazalides
LOR- infections, infections of upper respiratory tracts, gynecological infections, skin and soft tissues infections; ulcer disease; dyphteria; whooping-cough; honorrhea; syphilis; typhoid fever (azithromycin).
Drugs of choice for: mycoplasma, chlamidia, legionella pneumonia
Side affects of mSide affects of maacrolidescrolides
Dispeptic disorders, disbacteriosis, superinfectionDispeptic disorders, disbacteriosis, superinfection Cholestasis, cholestatic jaundice (erythromycin)Cholestasis, cholestatic jaundice (erythromycin) Depression of liver microsome enzyme activity Depression of liver microsome enzyme activity
(erythromycin, oleandomycin can not be combined (erythromycin, oleandomycin can not be combined with theophylline, ergot alkaloids, carbamazepine)with theophylline, ergot alkaloids, carbamazepine)
Development of resistance in process of treatmentDevelopment of resistance in process of treatment
Linkosamides Linkosamides
Linkomycin ClindamycinLinkomycin Clindamycin
Action spectrum: Gram positive aerobe cocci, Action spectrum: Gram positive aerobe cocci, grampositive and gramnegatvie anaerobesgrampositive and gramnegatvie anaerobes
Penetrate all the tissues (don’t pass through Penetrate all the tissues (don’t pass through HEB) including intracellurally HEB) including intracellurally
Usage: usually in Usage: usually in heavyheavy infections, caused by infections, caused by anaerobe microorganismsanaerobe microorganisms
A lot ofA lot of side side eeffectsffects
TetracyclinesTetracyclines
1. 1. Natural - biosynthetic:Natural - biosynthetic: chlortetracycline, oxytetracycline, chlortetracycline, oxytetracycline, tetracycline, tetracycline, dimethylchlortetracycline.dimethylchlortetracycline.
2. 2. SemiSemisyntheticsynthetic::
doxycycline (vibramycin), metacycline doxycycline (vibramycin), metacycline (rondomycin), minocycline.(rondomycin), minocycline.
Shemes of tetracyclines Shemes of tetracyclines administrationadministration
Tetracycline - 0,25-0,5 g 4 times per 24 Tetracycline - 0,25-0,5 g 4 times per 24 hours hours
Methacycline – 0,3-0,6 g 2 times per 24 Methacycline – 0,3-0,6 g 2 times per 24 hourshours
Doxycycline – 0,2 g (first day), 0,1g (next Doxycycline – 0,2 g (first day), 0,1g (next days) 1 time per 24 hoursdays) 1 time per 24 hours
Pharmacokinetics of tetracyclines when combined with Pharmacokinetics of tetracyclines when combined with other drugsother drugs
Drugs Results of combined administration
Antacides (Ca+, Mg+ Antacides (Ca+, Mg+ etc.)etc.)
Iron preparationsIron preparations
Rifampicin Rifampicin
Decrease of absorbtionDecrease of absorbtion
Decrease of absorbtionDecrease of absorbtion
Increase of eliminationIncrease of elimination
Side Side eeffects of tetracyclinesffects of tetracyclines Dispeptic disorders, stomatitis, glositis,esophagitis, Dispeptic disorders, stomatitis, glositis,esophagitis,
pruritus etc). pruritus etc). Disbacteriosis and superinfection with Candida fungi, Disbacteriosis and superinfection with Candida fungi,
proteus, pseudomonadas or staphylococci. proteus, pseudomonadas or staphylococci. Photodermatosis. Photodermatosis. Liver toxicity. Liver toxicity. Absorbtion by bones and teeth of a featus or a child: Absorbtion by bones and teeth of a featus or a child:
hipoplasia of dental enamel, disorder of teeth hipoplasia of dental enamel, disorder of teeth formation, tendency for caries. formation, tendency for caries.
Antianabolic action, damage of kidneys (when using Antianabolic action, damage of kidneys (when using tetracyclines with long termed storage, using big tetracyclines with long termed storage, using big doses).doses).
Tetracyclines are forbidden for children under the age of Tetracyclines are forbidden for children under the age of 88/12/12, during pregnancy, liver diseases, kidney , during pregnancy, liver diseases, kidney
insufficiency, miasteniainsufficiency, miastenia
AMINOGLYCOSIDESAMINOGLYCOSIDES
І generation:І generation: streptomycin, streptomycin, neomycin, monomycin, kanamycinneomycin, monomycin, kanamycin
ІІ generation:ІІ generation: gentam gentamyycin cin (garamycin), tobramycin, syzomycin(garamycin), tobramycin, syzomycin
ІІІ generation:ІІІ generation: netilm netilmyycin cin (netromycin), amikacin. (netromycin), amikacin.
spectrum of spectrum of aaction ction of of aminoglycosidesaminoglycosides
widewide 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 usage of aminoglycosidesIndications for usage of aminoglycosides
- at the beginning stage of infectious processes of unknown at the beginning stage of infectious processes of unknown ethiology and severe complexity (combined with beta-ethiology and severe complexity (combined with beta-lactamase); lactamase);
- considerable purulent-inflammatory component of heavy - considerable purulent-inflammatory component of heavy infections (peritonitis, sepsis, mediastinitis, abscesses and infections (peritonitis, sepsis, mediastinitis, abscesses and flegmones of soft tissues);flegmones of soft tissues);
- acute attack of chronical purulent-inflammatory diseases, - acute attack of chronical purulent-inflammatory diseases, including secondary immune defficiency;including secondary immune defficiency;
- early stage of development of secondary bacterial - early stage of development of secondary bacterial meningitis;meningitis;
- bacterial endocarditis;- bacterial endocarditis;- infections of urinary tracts;- infections of urinary tracts;- for prophilaxis of postoperative pustural complications - for prophilaxis of postoperative pustural complications
(combined with beta-lactamase antibiotics, metronidazole (combined with beta-lactamase antibiotics, metronidazole or other antianaerobe drugs);or other antianaerobe drugs);
- skin infections and subcutaneous fat tissue infections, burns.- skin infections and subcutaneous fat tissue infections, burns.
Concentration of aminoglycosides in Concentration of aminoglycosides in blood should not overcome:blood should not overcome:
Amikacin, kanamycin –Amikacin, kanamycin –
35-40 mkg/ml35-40 mkg/mlGentamicin, tobramycin –Gentamicin, tobramycin –
10-12 mkg/ml10-12 mkg/ml
Complications in administration of Complications in administration of aminoglycosidesaminoglycosides
Ototoxicity Ototoxicity Nephrotoxicity Nephrotoxicity NeurotoxicityNeurotoxicity
According to extent of toxicityAccording to extent of toxicitynetilmicin < gentamicin <tobramycin < netilmicin < gentamicin <tobramycin <
amikacin < neomycin < streptomycin < amikacin < neomycin < streptomycin < monomycin < kanamycinmonomycin < kanamycin
Leuko-, thrombocytopenia, hemmorhages, Leuko-, thrombocytopenia, hemmorhages, hemolisishemolisis
Allergic reactionsAllergic reactions
Chloramphenicol – Chloramphenicol – levomycetinlevomycetin
Indications:Indications:
meningitis, typhoid fever, paratyphoid fever, meningitis, typhoid fever, paratyphoid fever, brucellosis, tularemiabrucellosis, tularemia
Side Side eeffects:ffects: Hypochrome and aplastic anemiaHypochrome and aplastic anemia Granulocytopenia, thrombocytopeniaGranulocytopenia, thrombocytopenia «Grey syndrome of a featus»«Grey syndrome of a featus» Disbacteriosis and superinfectionDisbacteriosis and superinfection