Typical Peak Tissue Levels of Ceftazidime After 2g IV Doses · •Sulfonamides and trimethoprim...

Antibiotics

Antibiotics – mode of action

• Interference with of bacterial wall synthesis -

(betalactams, glycopeptides)

• Interference with DNA synthesis - (gyrase inhibitors)

• Antimetabolites - (sulfonamides, trimethoprim)

• Interference with proteosynthesis on various levels

– prevention of tRNA link (tetracycline)

– mRNA reading failure (aminoglycosides)

– Inhibition of transpeptidation (chloramphenicol)

– Inhibition of tRNA translocation (erythromycin)

Resistance

• Natural (target structure not present)

• Acquired

– Chromosomal - mutations - rare

– Extra chromosomal - plasmids - frequent

• plasmids – segments of DNA with ability of

independent replication carrying gens coding

resistence

– Transfer – conjugation of bacteria - plasmids

– Transduction by means of fags

– Transposes - plasmid/plasmid,

plasmid/chromosome and vice versa

– Transformation - DNA

Antibiotics - biochemical mechanisms of resistance

• Production of inactivating enzymes

– betalactamases - (penicillins, cefalosporins)

– acetyltransferases - (chloramphenicol)

– kinases - (aminoglycosides)

– methylases - (tetracyclines)

• Alteration of binding site - (betalactams, macrolides,

aminoglycosides)

• Reduction of antibiotic uptake - (tetracyclines)

• Alteration of dihydrofolat reductase - (sulfonamides)

• Efflux pumps - (more groups of antibiotics)

• Change in bacterial wall permeability - (betalactams)

Bacterial wall: G+ bacteria

Bacterial wall: G- bacteria

Penetration of IV. generation cephalosporins

accross bacterial wall in G- bacteria

Penetration of antibiotics across bacterial wall

in G- bacteria

Hypothetic structure of efflux pump

Beta-lactams

1929

1941

1944

objev penicilinu

začátek používání

penicilinu

první b-laktamázy

Od objevu penicilinu k širokospektrým

b-laktamům

A. Fleming, W. Florey, E. B. Chain – 1945 Nobelova

Cena za Fyziologii a medicínu Za objev penicilinu

a jeho léčivého účinku na různé infekční choroby

penicilin G penicilin V

semisyntetické

peniciliny 1960

1957

1948 1947

methicilin 1960

ampicilin 1961

kloxacilin 1963

karbenicilin 1967

pivampicilin 1970 ...

6-APA


b-laktamům

amoxicilinklavulanát 1981

1977

1973 amoxicilin

kyselina

klavulanová


b-laktamům

Pharmacokinetics of penicillins

Penicillin Clearance (l/h)

t1/2

(h)

VD

(l/kg)

Protein binding (%)

Benzathinpenicillin 30,0 0,5 0,5 80

Benzylpenicillin 30,0 1,0 0,3 65

Amoxycillin 25,0 1,2 0,4 18

Ampicillin 13,0 1,0 0,4 18

Oxacillin 27,0 0,6 0,4 94

Azlocillin 9,0 1,0 0,2 30

Piperacillin 10,0 1,0 0,2 50

Tikarcillin 9,0 1,2 0,2 60

Antibacterial spectrum

Standard pk Nonstandard PK Metabolic instability

G+ Cefazolin Cefradin (p.o., i.v., i.m.)

Cefalotin (deacetyl)

G(+)/- Cefuroxim Ceftriaxon (t0,5, bile)

Cefotaxim (deacetyl)

G- Ceftazidim Cefoperazon (bile)

/

anaerobes cefoxitin Cefotetan (t0,5)

/

Division of cephalosporins according to

pharmacokinetic properties (examples)

Absorption and bioavailability (F) of

esterified cephalosporins

Influence of food intake on absorption of

esterified cephalosorins

mg/l

h

After food

No food

Beta-lactam distribution and volume of

distribution

ICF

80 %

intravascular compartment

interstitium connective tissue GIT

extravascuar compartment

ECF

20 %

TBF

100%

Plasma, intersticium and muscle

concentration of ceftazidim (25 mg/kg i.v.)

mg/l * mg/kg

min

Drug concentration – fast transport between

vascular and extra vascular space

Drug concentration – slow transport between

vascular and extra vascular space

Penetration of cephalosorins across

hematoencephalic barrier in meningitis

(% of serum concentration)

cephalosporin penetration into CSF

ceftriaxon 5 - 15

cefotaxim 15 - 30

ceftazidim 20 - 40

cefuroxim 18 - 35

Penetration above 10% is clinically sufficient

Drug concentration – transport accross

blood-brain barrier

Penicilin

Concentration ratio bile / plasm

penicilin-G 0,5 Ampicilin 1,0 - 2,0 Karbenicilin 0,5 - 0,8 Methicilin 0,2 - 0,5 Mezlocilin 10,0 Nafcilin 40,0 Oxacilin 0,2 - 0,4 Dikloxacilin 0,05 - 0,08 Piperacilin 10,0 -15,0

Bile excretion of penicilins

(without obstruction)

Penetration above 0,5 (50%) is clinically sufficient

Bile excretion of cephalosporins


Concentration ratio

bile: plasm

Penetration above 0,5 (50%) is clinically sufficient

Elimination half life (t0,5) and dosage

interval in parenteral cephalosporins 1 x d 2 x d 3 x d

h h

h

2 x d 3 x d 4 x d


interval in parenteral cephalosporins

h

3 x d 2 x d 1 x d


interval in oral cephalosporins

GFR (ml/min)

t0,5b (h)

Relationship between t0,5 and GFR in

cephalosporins (example ceftazidim)

Macrolides

Site of proteosyntetic inhibition on ribosome

RNA polymerase

Subunit 30S

mRNA

30S iniciating complex


Creation of peptidic link

Subunit 50S

Peptidyl transferase

Rifampicin

Aminoglycosides

Chloramphenicol

Makrolides, clindamycin

Peptide elongation

Tetracyklins, glycylcyklins

Pharmacokinetics of erythromyci and its esters after

single p.o. dose (expressed as erythromycine basis)

Erythromycin D (mg) Cmax (mg/l)

Tmax (h) t0,5 (h) AUC (mg x h/l)

Basis 500 2,00 3,7 2,0 7,7

Stearat 500 2,43 1,8 1,9 8,8

Ethylsukcinat 500 1,19 1,1 1,7 4,5

Acistrat 400 2,23 2,6 3,0 12,3

Plasma and tissue concentration of azithromycin

risk of resistance

Influence of renal and liver function and age

on macrolide PK

Serious renal failure

Serious liver failure

Age

erythromycin ? 0 ?

klarithromycin ++ 0 +

roxithromycin ++ ++ ++

azithromycin 0 - 0

0 no clinical changes

- data not available, probably no changes

+ data not available, probably elevated plasma levels

++ significantly elevated plasma levels, elavated Cmax, AUC and

extended t05,

? not reliable results

Interaction of macrolides according to

clinical significance

Teofylin Karbamazepin Ciklosporin Terfenadin Warfarin Ergotamin Methyl- prednisolon

Erythromycin ++ ++ ++ ++ ++ ++ ++

Klarithromycin + + + ++ n ++ n

Roxithromycin + 0 + n 0 n n

Azithromycin 0 0 n 0 0 n 0

++ clinically significant

+ influence on PK with potential clinical consequences

0 – interactions not observed

n – data not available

Macrolide (=drug A) interaction with other drugs

metabolised by cytochrome P 450

drugB Resulting interaction (A+B)

Teofylin Serum concentration increase (B)

ciklosporin, takrolimus, sirolimus (Enzyme inhibition)

Digoxin

Astemizol, terfenadin, loratadin

Námelové alkaloidy

Kortikosteroidy

Cisaprid

Midazolam, triazolam

Diltiazem, verapamil

Ethynil estradiol, destoden

Itrakonazol, mikonazol, ketokonazol, flukonazol

Fluoxetin, paroxetin, sertalin

Warfarin

indinavir, ritonavir Serum concentration increase (both A and B)

fenytoin, fenobarbital, karbamazepin

Omeprazol

rifabutin, rifampicin

Zidovudin Serum concentration decrease (B)

(Enzyme induction)

Cytochrome P 450 and macrolides

Enzym

Inhibitor Induktor

CYP1A2 macrolides – erythromycin, troleandomycin, klarithromycin, roxitromycin, diritromycin chinolones – but not all chinolones [Andriole] estrogeny – ethynilestradiol ethanol

Omeprazol Antiepileptika – fenytoin, fenobarbital, karbamazepin

CYP3A4 makrolides – erythromycin, troleandomycin, klarithromycin, roxitromycin, diritromycin chinolony – but not all chinolones [Andriole] imidazoly – ketokonazol, itrakonazol, flukonazol, antidepresiva – SSRI (fluoxetin, paroxetin, sertalin and others), grapefruit juice

rifampicin antiepileptika – fenytoin, fenobarbital, karbamazepin troglytazon

Seriousness of patients condition and clinical

perception of resistance

kritický

• Macrolide of the ketolide group

• Mode of action, AE profile and

interactions (CYP 3A4 a CYP 2P6) –

same as other macrolides

Telithromycin

Postantibiotic effect (PAE) in selected

makrolides – Staphylococcus aureus

Macrolid (exposure 2 h)

Concentration mg/l

Testing dose PAE (h)

erythromycin 0,50 4 – 5 x MIC 3,1

klarithromycin 0,25 4 – 5 x MIC 2,9

azithromycin 0,50 4 – 5 x MIC 2,5

Mechanism of resistance

S. pyogenes and S. pneumoniae to macrolides

• erm gens (production of methylase rRNA,

postranslation methylation 23S rRNA)

• Constitutive resistance (erm gens - chromosomal)

– MLSB resistance (macrolides, lincosamides,

streptogramin B)

• Inducibile resistance (erm gens - plazmids)

– Resistance to macrolides - 14 and 15 membered lactone

ring, low resistance to 16 membered lactone ring

macrolides and lincosamides

• mefA gen (eflux of antibiotic)

• Resistance to 14 and 15-membered lactone ring macrolides

- M fenotyp

End of part 1

Tetracyclins

Site of proteosyntetic inhibition on ribozome

RNA polymerase

Subunit 30S

mRNA



Creation of peptidic link

Subunit 50S

Peptidyl transferase

Rifampicin

Aminoglycosides

Chloramphenicol

Makrolides, clindamycin

Peptide elongation

Tetracyklins, glycylcyklins

Tetracyclins - characteristics

• Broad spectrum bakteriostatic antibiotics

introduced in1949 oxyteracyclin (I. generation),

doxycyclin since1967 (II. genaration)

• Mode of action - proteosyntetic inhibitors in

bacteial cell

• Many bacteria straine resistent – result of

frequent use

• Tetracyclins inhibit tRNA-aminoacids

complex link on 30s bacterial ribosome

subunit

• Tetracyclins prevent the link aminoacyl-tRNA

on acceptor site of the mRNA complex with

ribosome

Tetracyclins - mode of action

Tetracyclins - resistance

• Plasmid resistance

• Gen for tetracycline resistance is close to

gen coding resistance to aminoglycosides,

sulfonamides a chloramphenicol

• Cross resistance with this ATBs frequent

• Decrease of accumulation or decrease

of influx resp. increase of efflux

• Limited contact of TTC with ribosome

due to ribosomal protective proteins

• Enzymatic inactivation by methylase

Tetracyclins - mechanism of resistance

Tetracyclines - pharmacokinetics

• Irregular absorption – in small intestine -

better fasting

• Protein binding +/- 80%

• Penetrate placentar barrier and into maternal

milk!

• Bile excretion - enterohepatic circulation

• Partly eliminated via kidney

Tetracycline - antimicrobial spectrum

• S. pneumoniae - frequently resistant

• H. influenzae, E. coli - frequently resistant

• Vibrio cholerae

• Chlamydia, Mycoplasms

• Shigella – if sensitive

• Ureaplasma

• Rickettsie

• Brucela, Listeria, Yersinia

• Actinomycetes

• Protozoar infection (amoeba, malaria-schizonts)

Average resistance to selected antibiotics

S. pneumoniae

Resistance (%)


S. pyogenes

Resistance (%)

1992 1993 1994 1995 1996

Number of isolates

778 768 826 975 701

Doxycyclin 15,7 12,9 29,1 23,4 20,5

Chloramphenicol 12,3 15,2 19,5 18,4 13,8

Co-trimoxazol 27,4 30,7 42,5 39,7 34,0

Ofloxacin 6,4 2,7 7,0 4,3 3,6

Prevalence of resistance to selected antibiotics in EU

S. pneumoniae (1992 - 1996)


H. influenzae

Resinstance (%)

1992 1993 1994 1995

Number of isolates/bla+

702/12,3% 1130/14,4% 1065/15,5% 1456/16,8%

Chloramphenikol 4,1 2,5 2,5 2,1

Co-trimoxazol 13,5 8,6 20,5 18,9

Average resistence to selected antibiotics in EU

H. Influenzae (1992 - 1995)

Tetracyclines – ADR and KI

• ADR

– GI - frequent, alter compliance,

pseudomembranous colitis rare

– Most serious - toxic liver damage

– Exfoliative dermatitis

– Fotosenzibilisation - fotodermatitis

• KI

– pregnancy a lactation

– children until 8 years – dental abnormities

– alcohol

Tetracyclines - interactions

• Pharmacokinetic on the level of absorption - antacids,

Ca, Mg, Zn, Al and other salts, milk and milk products

– decrease of absorption (chelats)

• Coumarin anticoagulation drugs – increase of

bleeding

• OHA - hypoglycemia

• Interaction with cytochrome P450 - metabolism of

tetracycline accelerated = decrease of therapeutic

concentration

• Combining with beta-lactams = decrease in efficacy!

Antimetabolites

• Sulfonamides and trimethoprim block two

subsequent processes of nucleic acid synthesis

• Sulfonamides compete with PABA for

dihydropteroate syntetase necessary for

dihydrofolic acid synthesis

• Trimethoprim is competitive inhibitor of

dihydrofolatreductase preventing conversion to

tetrahydrofolic acid

Antimetabolites – mode of action

• In sulfonamides: plasmid encoded

dihydropteroate synthetase with low affinity to

sulfonamide (but preserved to PABA)

• In trimethoprim: bypass of metabolic pathway

dihyhydrofolat reductase has then low affinity

to trimethoprim

Antimetabolits – mechanisms of rezistance

• Gastrointestinal – nausea, vomitus

• Dermal – from mild up to toxic epidermal

necrolysis

• Hematological dosorders

• Caution: asthma, serious allergic disorders and

liver function disorders

• Contraindications: pregnancy, brest feeding,

immature neonates

Antimetabolites - AE, contraindications

• Frequent PK interactions – binding site

competition in plasma proteins (oral

hypoglycemic agents, anticoagulating agents)

• Antacids decrease antibacterial efficacy

• NSAID (aspirin) in combination with

sulfonamides = crystaluria

• Sulfonamides and TMP are fenytoin

metabolism inhibitors (t0,5 extension by 40%)

Antimetabolites – interactions

Consumption of broad spectrum ATB in DDD

x x

x x

x) only co-trimoxazol a co-amoxicillin

Amphenicols

Chloramphenicol - characteristics

• First synthetic ATB (1947)

• Broad spectrum bacteriostatic ATB

• Proteosynthetic inhibitor on 50S subunit

• Prevents incorporation of amino Ac into

newly synthesized peptides

• Spectrum: H. influenzae, N. meningitidis,

Bacteroides

• Indication – salmonella infections,

H. influenzae meningitis, sepsis including

anaerobic

Chloramphenicol - AE/IT

• Blood disorders

– Early: reversible, dose dependent, given by

means of Mode of action

– Delayed: irreversible - idiosyncrasy - aplastic

anemia with lethal outcome

• Grey children syndrome – alteration of

detoxicatoin (glucuronidation)

• Interaction – cytochrome P450

– OHA (PAD), phenytoin, warfarin – incerase of

plasma levels

Aminoglycosides

Aminoglycosides – characteristics (1)

• Broad spectrum bactericidal ATBs

• Mode of action – proteosynthetic

inhibition

• No oral absorptions - only parenteral

application possible

• Renal elimination - in RI dose

adjustment needed

• Do not penetrate BBB

Aminoglycosides – characteristics (2)

• Significant post antibiotic effect (PAE)

• Single daily dose = decrease of toxicity

• Toxicity depends more on length of

exposure then on height of dose

Aminoglycosides – mode of action

• Proteosynthetic inhibitor on 30S

ribosome subunit

• Alteration of recognition

codon/anticodon = wrong reading mRNA

= synthesis of incorrect bacterial

proteins

Aminoglycosides - resistance

• Inactivation of aminoglycoside by means of

microbial enzymes - 9 enzymes (plasmid encoded

resistance) netilmycin and amicacin are not

metabolized

• Metabolite does not interfere with proteosyntesis

• Alteration of penetration across bacterial wall –

prevented by means of combination with

penicillin or vancomycin

• Mutation of 30S subunit (streptomycin)

Aminoglycosides - antibacterial spectrum

• G- including P. aeruginosa

• Poor H. influenzae, Mycoplasms

• G+ less or not effective

• No effect (Bacteroides)

• Some AMG act as antituberculotics

(streptomycin)

Aminoglycosides - compounds

• Amicacin, gentamycin, tobramycin,

netilmycin, isepamycin

• Streptomycin, kanamycin

(antituberculotics)

• Neomycin (topical use in surgery - lavage)

• Spectinomycin (single dose - gonorrhea)

Aminoglycosides - AE

• Nephrotoxicity (reversible)

• Ototoxicity (irreversible)

• Neurotoxicity

• Curare-like effect (streptomycin)

• Worsening of AE - diuretics, dehydratation

• AE – depend on plasma level

• Plasma level estimation frequently necessary

Glycopeptides

Glycopeptides – mode of action (1)

Basic component of peptidoglycan: N-acetyl-

glukosaminmuramyl-pentapeptid.

• Transglycosilase, transpeptidase and D,D-

carboxypeptidase are responsible for building of

macromolecular structure .

• Transglycosilase connects muramyl parts

• Transpeptidase connects transversal links by means

of cleaving end alanin on both ends of the chain

• D,D - karboxypeptidase cleavs end D - ala and acts

as regulator

• Inhibit peptidoglycan growth (early phase of cell wall

synthesis of G+ microbes: conjugation with new

components of bacterial wall).

• Beta-lactams: late phase of synthesis – creation of

transversal links

• Beta-lactams act by means of PBP, glycopeptides on

substrate

• PAE vanco 1 - 2 h, teico 2 - 10 h

• Glycopeptides are active only against G+ (c.f. MoA)

• Combination with b-lact., Ag., Chino., Rif. possible

Glycopeptides – mode of action (2)

Most frequent: enterococci - Van A, B, C

• Van A: inducible van and teico - genetic

alteration, D - ala replaced by. D - lactate or D -

butyrate, gen transferred by means of

conjugation

• Van B: only in van. In genetically equipped

bacteria. Induced by low concentration of van.

Non plasmid.

• Van C: Chromosomal, only in van, insignificant

Glycopeptides - resistance

Fluorochinolones

Etiology of AECB

Sethi et al. Chest 2000;117:380s-385s

80% infectious

20% Non infectious

40 - 50% Bacterial patogens 30 - 40% Viroval infections 5 - 10% Atypical bacteria

Environmental factors Non-compliance

Chinolones and fluorochinolones optimum

structure - optimum antimicrobial activity

1. Substitution on N1 (best cyclopropyl)

2. Double link between C2 and C3

3. On C3 carboxyl group

4. On C4 keto group

5. On C6 fluorine atom

6. On C7 substitution, most frequently piperazin,

resp. N4´ methyl piperazin (G-) or pyrolidin (G+)

Replication

Classification of chinolones (Andriole 1998)

Nonfluorinated (I)

Fluorinated (II)

Fluorinated (III)

Fluorinated broad

spectrum (IV)

nalidixic ac. pipemidic ac. oxolinic ac. rosoxacin

norfloxacin ciprofloxacin ofloxacin pefloxacin enoxacin lomefloxacin fleroxacin rufloxacin

levofloxacin gatifloxacin sparfloxacin grepafloxacin temafloxacin

gemifloxacin sitafloxacin moxifloxacin clinafloxacin trovafloxacin alatrofloxacin*

*prodrug of trovafloxacin

Absorption - Cmax and

bioavailability (F) of fluorochinolones Chinolon Dose (mg) Cmax (mg/l) F (%)

norfloxacin ciprofloxacin ofloxacin pefloxacin enoxacin lomefloxacin fleroxacin rufloxacin levofloxacin sparfloxacin grepaflpxacin trovafloxacin gatifloxacin clinafloxacin gemifloxacin moxifloxacin

400 500 400 400 400 400 400 400 500 400 400 300 400 400 600 400

1,5 2,5 4,0 3,2 2,3 3,5 4,3 3,2 5,1 1,6 1,3 3,6 3,3 2,4 3,9 2,5

45 85 95 95 88 95 92 50 99 90 72 88 96 90 95 89

Fluorochinolone distribution and volume of

distribution

ICF

80 %

intravascular compartment

interstitium connective tissue GIT

extravascular compartment

ECF

20 %

TBF

100%

FCH Dose (mg) Binding (%) VD (l)


400 500 400 400 400 400 400 400 500 400 400 300 400 400 600 400

14 35 25 30 40 10 23 70 35 45 50 70 20 55 70 48

225 195 102 112 175 133 110 149 101 350 560 84

118 150

* 250

Distribution of fluorochinolones (VD) and

protrin binding (plasma albumin)

Concentration of norfloxacine in plasma,

interstitial fluid and tissue (15 mg/kg i.v.)

mg/l * mg/kg

min

tissue

interstitial fluid

plasma

Bronchial mucose

epithelial film alveolar macrofages

fluorochinolones 1 – 3 : 1 3 – 12 : 1 10 – 34 : 1

b-lactams 0,40 : 1 0,25 : 1 0,10 : 1

macrolides 2 – 10 : 1 10 : 1 20 – 100 : 1

Respiratory tissue and fluid penetration of

fluorochinolones, ß-lactams, and macrolides

Concentration ratio tissue resp. fluid : blood plasma

Penetration, cumulation, localization

and efflux of the antibiotic from the cell

Antibiotics Penetration Cumulation Localization Efflux

aminoglycosides slow (days) very slow lysozomes very slow

b-laktams weak není cytosol fast

fluorochinolones fast 4 – 8 x cytosol fast

macrolides slow up to 100 x lysozomes cytosol

slow

Penetration of fluorochinolones across

BBB (man)

Ratio above 0,1 is clinically sufficient

Concentration ratio likvor : plasma

Inflamated

Normal

Penetration of fluorochinolones across

BBB (model)

Concentration ratio likvor : plasma


Inflamated

Normal

Bile excretion of fluorochinolones


Concentration ratio bile : plasma


Elimination pathways of fluorochinolones

• Kidney

–ofloxacin, levofloxacin, lomefloxacin,

fleroxacin, rufloxacin, clinafloxacin,

gatifloxacin

• Liver

–pefloxacin, grepafloxacin

• Kidney + liver

–trovafloxacin, enoxacin, norfloxacin

• Kidney + liver + GIT

–ciprofloxacin, sparfloxacin

Chinolon Dose (mg) Clr (ml/min) Fu (%)


400 500 400 400 400 400 400 400 500 400 400 300 400 400 600 400

234 358 195 20

193 189 105 20

125 25 47 8

170 200 141 51

27 65 73 15 44 66 50 50 70 40 9 6

85 60 32 20

Elimination of FCH - cumulative %

eliminated into urine (Fu) in 72 h

Elimination half lives (t0,5) of FCH

h

2 x d (b.i.d.) 1 x d (o.d.)

FCH requiring dose resp. interval adjustment

in altered renal function

Fluorochinolon Usual interval Interval adjustment resp. dose

CLcr > 1,5 (ml/s)

CLcr 0,15-0,8 (ml/s)

CLcr < 0,15 (ml/s)

norfloxacin ciprofloxacin ofloxacin enoxacin fleroxacin levofloxacin lomefloxacin sparfloxacin

12 h 12 h 12 h 12 h 24 h 24 h 24 h 24 h

24 h 18 h 24 h

½ d á 12 h ½ d á 24 h ½ d á 24 h ½ d á 24 h ½ d á 24 h

24 h 24 h

½ d á 24 h ½ d á 24 h ½ d á 48 h ½ d á 48 h ½ d á 24 h ½ d á 24 h

ATB AUC0-24 MIC 90 AUIC AUC0-24 MIC 90 AUIC

A 125,0 1,0 125,0 125,0 2,0 62,5

B 320,0 2,0 160,0 320,0 8,0 40,0

A+B - - 285,0 - - 102,5

PK – PD relationship and antibiotic

combination

A and B are antibiotics with different mode of action

Duration of PAE* (h)

Antibiotics Staphylo-coccus spp.

Entero-bacteriaceae

Pseudomonas

Penicilins – 2 0,5 – 2 0,5

Cefalosporins – 2 0,5 – 2 0,5

Aminoglykosides 2 – 4 2 – 6 2 – 6

Macrolides 3 – 6 3,5 – 6 –

Fluorochinolones 2 – 4 2 – 6 2 – 6

*Extention of suppression of bacterial growth after short

Exposure to antibiotics in vitro

Number of patients needed to record rare B

type AE*

Incidence 1 2 3

1 : 100 300 480 650

1 : 200 600 900 1 300

1 : 1 000 3 000 4 800 6 500

1 : 2 000 6 000 9 600 13 000

1 : 10 000 30 000 48 000 65 000

* AE type A given by pharmacological – predictable

AE type B are rare – non predictable

AE of fluorochinolones highest dose without

fototoxicity (mg/kg)*

(log conc..)

*experimental data Andriole, 1998

18

AE of fluorochinolones inhibition of link to GABA receptor on presence of NSAID*

(log inhib.)

*drug interaction with potential cramps, experimental data - Andriole, 1998

• Hepatotoxicity - trovafloxacin (B)

• Elongation of QT interval - grepafloxacin (?)

• Temafloxacine syndrom - temafloxacin (B),

• Hypoglycemia - clinafloxacin (B)

• Phototoxicity - sparfloxacin (A)

• Artropathy in exp. Animals - all ch. (A)

Some AE of chinolones

• Elongation of QT interval : without relation to

P450 mainly in predisposed, incidence 3,7: 1M,

improper combination with e.g. cisapride,

astemizole and terfenadine

• Temafloxacine sy.: hemolytic - uremic syndrome

probably immune reaction, incidence 1: 1000

• Artropathy: probably based on generation of

chelates, mainly uptake of Mg++ creation of

radicals alteration of chondrocytes

Some AE of chinolones

Interaction of chinolones

Concomitant medication (B)

Result of interaction (A+B)

antacids containing Mg, Al

sucralfat, Bi Decreased of bioavailability

Fe, Ca of chinolone (A)

H2 antihistamines*

*metabolised by cytochrome P450

Responsibility for interactions is attributed to piperazin on C6,

Methylation of piperazin results decrease of interactions

Interaction of chinolones „drug (A)“

Concomitant medication (B)

Result of interaction (A+B)

theofylin, caffeine

digoxin, warfarin increased plasma

glibenclamid concentration of drug (B)

opioids

Interaction of chinolones: influence on enzyme

activity of various isoforms of cytochrome P450

Isoform Inhibitor Inducer

CYP1A2 chinolones: pipemidic ac., enoxacin, grepafloxacin, pefloxacin, ciprofloxacin, ofloxacin

rifampicin

14C macrolides: erythromycin, klarithromycin, roxirthromycin, dirithromycin

CYP3A4 chinolony rifampicin

14C macrolides imidazoly: ketokonazol, itrakonazol, flukonazol

Interaction with theofylin increase of

theofylin Cmax and AUC

(%)

• Oxazolidinon – proteosyntetic inhibitor (binds

on 23s subunit 50s – prevents 70s complex

necessary for translation

• Bioavailability p.o. – 100%

Linezolid

Linezolid

• Selective proteosyntetic inhibitor a non-

selective MAO inhibitor - oxazolidin

• Indication G+ infection, including serious

nosocomial

• G+ including MRSA and VRE a PNC/ERY

resistant streptococci

• In mixed G+/G- infection combination

necessary

• Non cross resistance VRSA and MRSA

• No activity in atypical microorganisms

• Recommended only by ATB centers

• KI cf. interaction with iMAO

Typical Peak Tissue Levels of Ceftazidime After 2g IV Doses · •Sulfonamides and trimethoprim...

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Transcript of Typical Peak Tissue Levels of Ceftazidime After 2g IV Doses · •Sulfonamides and trimethoprim...