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 Od objevu penicilinu k širokospektrým b-laktamům

1944 první b-laktamázy 1941 začátek používání penicilinu

1929 objev penicilinu

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 Od objevu penicilinu k širokospektrým b-laktamům methicilin 1960 ampicilin 1961 kloxacilin 1963 karbenicilin 1967 pivampicilin 1970 ... 1960 semisyntetické peniciliny 1957 6-APA

1948 penicilin V 1947 penicilin G Od objevu penicilinu k širokospektrým b-laktamům

1981 amoxicilinklavulanát 1977 kyselina klavulanová

1973 amoxicilin Pharmacokinetics of penicillins

Penicillin Clearance t1/2 VD Protein binding (%) (l/h) (h) (l/kg) 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

Division of cephalosporins according to pharmacokinetic properties (examples)

Antibacterial Standard pk Nonstandard PK Metabolic spectrum instability G+ Cefazolin Cefradin Cefalotin (p.o., i.v., i.m.) (deacetyl) G(+)/- Cefuroxim Ceftriaxon Cefotaxim (t0,5, bile) (deacetyl) G- Ceftazidim Cefoperazon / (bile) anaerobes cefoxitin Cefotetan / (t0,5)

Absorption and bioavailability (F) of esterified cephalosporins Influence of food intake on absorption of esterified cephalosorins mg/l

After food

No food

h Beta-lactam distribution and volume of distribution

TBF 100%

ICF ECF 80 % 20 %

intravascular compartment extravascuar compartment

interstitium connective tissue GIT 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

Bile excretion of penicilins (without obstruction)

Concentration ratio Penicilin 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

Penetration above 0,5 (50%) is clinically sufficient Bile excretion of cephalosporins (without obstruction)

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 hh Elimination half life (t0,5) and dosage interval in parenteral cephalosporins

2 x d 3 x d 4 x d h Elimination half life (t0,5) and dosage interval in oral cephalosporins 3 x d 2 x d 1 x d h Relationship between t0,5 and GFR in cephalosporins (example ceftazidim)

t0,5b (h)

GFR (ml/min) Macrolides RNA polymerase Rifampicin mRNA Subunit 30S Tetracyklins, glycylcyklins 30S iniciating complex Subunit 50S Aminoglycosides 70S iniciating complex Peptidyl transferase Chloramphenicol Creation of peptidic link Makrolides, clindamycin Peptide elongation

Site of proteosyntetic inhibition on ribosome Pharmacokinetics of erythromyci and its esters after single p.o. dose (expressed as erythromycine basis)

Erythromycin D (mg) Cmax Tmax (h) t0,5 (h) AUC (mg x h/l) (mg/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 Serious liver Age failure failure 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, Omeprazol klarithromycin, roxitromycin, diritromycin Antiepileptika – fenytoin, chinolones – but not all chinolones [Andriole] fenobarbital, karbamazepin estrogeny – ethynilestradiol ethanol CYP3A4 makrolides – erythromycin, troleandomycin, rifampicin klarithromycin, roxitromycin, diritromycin antiepileptika – fenytoin, chinolony – but not all chinolones [Andriole] fenobarbital, karbamazepin imidazoly – ketokonazol, itrakonazol, flukonazol, troglytazon antidepresiva – SSRI (fluoxetin, paroxetin, sertalin and others), grapefruit juice

Seriousness of patients condition and clinical perception of resistance

kritický Telithromycin

• Macrolide of the ketolide group • Mode of action, AE profile and interactions (CYP 3A4 a CYP 2P6) – same as other macrolides Postantibiotic effect (PAE) in selected makrolides – Staphylococcus aureus

Macrolid Concentration Testing dose PAE (h) (exposure 2 h) mg/l 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 RNA polymerase Rifampicin mRNA Subunit 30S Tetracyklins, glycylcyklins 30S iniciating complex Subunit 50S Aminoglycosides 70S iniciating complex Peptidyl transferase Chloramphenicol Creation of peptidic link Makrolides, clindamycin Peptide elongation

Site of proteosyntetic inhibition on ribozome 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 - mode of action

• 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 - resistance

• Plasmid resistance

• Gen for tetracycline resistance is close to gen coding resistance to aminoglycosides, sulfonamides a chloramphenicol

• Cross resistance with this ATBs frequent Tetracyclins - mechanism of resistance

• 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 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 (%) Average resistance to selected antibiotics S. pyogenes

Resistance (%) Prevalence of resistance to selected antibiotics in EU S. pneumoniae (1992 - 1996)

1992 1993 1994 1995 1996

Number of 778 768 826 975 701 isolates 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

Average resistance to selected antibiotics H. influenzae

Resinstance (%) Average resistence to selected antibiotics in EU H. Influenzae (1992 - 1995)

1992 1993 1994 1995

Number of 702/12,3% 1130/14,4% 1065/15,5% 1456/16,8% isolates/bla+ Chloramphenikol 4,1 2,5 2,5 2,1

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

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 Antimetabolites – mode of action

• 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 Antimetabolits – mechanisms of rezistance

• 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

Antimetabolites - AE, contraindications

• 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 – interactions

• 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%)

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 Glycopeptides – mode of action (2)

• 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 - resistance

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 Fluorochinolones Etiology of AECB

20% 80% Non infectious infectious

Environmental 40 - 50% factors Bacterial patogens

Non-compliance 30 - 40% Viroval infections

5 - 10% Atypical bacteria

Sethi et al. Chest 2000;117:380s-385s 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 Fluorinated Fluorinated Fluorinated (I) (II) (III) broad spectrum (IV) nalidixic ac. norfloxacin levofloxacin gemifloxacin pipemidic ac. ciprofloxacin gatifloxacin sitafloxacin oxolinic ac. ofloxacin sparfloxacin moxifloxacin rosoxacin pefloxacin grepafloxacin clinafloxacin enoxacin temafloxacin trovafloxacin lomefloxacin alatrofloxacin* fleroxacin rufloxacin

*prodrug of trovafloxacin Absorption - Cmax and bioavailability (F) of fluorochinolones

Chinolon Dose (mg) Cmax (mg/l) F (%) norfloxacin 400 1,5 45 ciprofloxacin 500 2,5 85 ofloxacin 400 4,0 95 pefloxacin 400 3,2 95 enoxacin 400 2,3 88 lomefloxacin 400 3,5 95 fleroxacin 400 4,3 92 rufloxacin 400 3,2 50 levofloxacin 500 5,1 99 sparfloxacin 400 1,6 90 grepaflpxacin 400 1,3 72 trovafloxacin 300 3,6 88 gatifloxacin 400 3,3 96 clinafloxacin 400 2,4 90 gemifloxacin 600 3,9 95 moxifloxacin 400 2,5 89

Fluorochinolone distribution and volume of distribution

TBF 100%

ICF ECF 80 % 20 %

intravascular compartment extravascular compartment

interstitium connective tissue GIT Distribution of fluorochinolones (VD) and protrin binding (plasma albumin)

FCH Dose (mg) Binding (%) VD (l) norfloxacin 400 14 225 ciprofloxacin 500 35 195 ofloxacin 400 25 102 pefloxacin 400 30 112 enoxacin 400 40 175 lomefloxacin 400 10 133 fleroxacin 400 23 110 rufloxacin 400 70 149 levofloxacin 500 35 101 sparfloxacin 400 45 350 grepaflpxacin 400 50 560 trovafloxacin 300 70 84 gatifloxacin 400 20 118 clinafloxacin 400 55 150 gemifloxacin 600 70 * moxifloxacin 400 48 250

Concentration of norfloxacine in plasma, interstitial fluid and tissue (15 mg/kg i.v.) mg/l * mg/kg

tissue interstitial fluid plasma

min Respiratory tissue and fluid penetration of fluorochinolones, ß-lactams, and macrolides

Bronchial epithelial film alveolar mucose 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

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 slow cytosol

Penetration of fluorochinolones across BBB (man)

Concentration ratio likvor : plasma

Inflamated Normal

Ratio above 0,1 is clinically sufficient Penetration of fluorochinolones across BBB (model)

Concentration ratio likvor : plasma

Inflamated Normal

Ratio above 0,1 is clinically sufficient Bile excretion of fluorochinolones (without obstruction) Concentration ratio bile : plasma

Ratio above 0,5 is clinically sufficient 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 Elimination of FCH - cumulative %

eliminated into urine (Fu) in 72 h Chinolon Dose (mg) Clr (ml/min) Fu (%) norfloxacin 400 234 27 ciprofloxacin 500 358 65 ofloxacin 400 195 73 pefloxacin 400 20 15 enoxacin 400 193 44 lomefloxacin 400 189 66 fleroxacin 400 105 50 rufloxacin 400 20 50 levofloxacin 500 125 70 sparfloxacin 400 25 40 grepaflpxacin 400 47 9 trovafloxacin 300 8 6 gatifloxacin 400 170 85 clinafloxacin 400 200 60 gemifloxacin 600 141 32 moxifloxacin 400 51 20

Elimination half lives (t0,5) of FCH

2 x d (b.i.d.) 1 x d (o.d.) h FCH requiring dose resp. interval adjustment in altered renal function

Fluorochinolon Usual interval Interval adjustment resp. dose

CLcr > 1,5 CLcr 0,15-0,8 CLcr < 0,15 (ml/s) (ml/s) (ml/s) norfloxacin 12 h 24 h 24 h ciprofloxacin 12 h 18 h 24 h ofloxacin 12 h 24 h ½ d á 24 h enoxacin 12 h ½ d á 12 h ½ d á 24 h fleroxacin 24 h ½ d á 24 h ½ d á 48 h levofloxacin 24 h ½ d á 24 h ½ d á 48 h lomefloxacin 24 h ½ d á 24 h ½ d á 24 h sparfloxacin 24 h ½ d á 24 h ½ d á 24 h

PK – PD relationship and antibiotic combination

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

A and B are antibiotics with different mode of action Duration of PAE* (h)

*Extention of suppression of bacterial growth after short Exposure to antibiotics in vitro

Antibiotics Staphylo- Entero- Pseudomonas coccus spp. bacteriaceae 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

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..)

18

*experimental data Andriole, 1998 AE of fluorochinolones inhibition of link to GABA receptor on presence of NSAID*

(log inhib.)

*drug interaction with potential cramps, experimental data - Andriole, 1998 Some AE of chinolones

• 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 Interaction of chinolones

Responsibility for interactions is attributed to piperazin on C6, Methylation of piperazin results decrease of interactions

Concomitant Result of interaction medication (B) (A+B) antacids containing Mg, Al sucralfat, Bi Decreased of bioavailability Fe, Ca of chinolone (A)

H2 antihistamines*

*metabolised by cytochrome P450 Interaction of chinolones „drug (A)“

Concomitant Result of interaction medication (B) (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, rifampicin grepafloxacin, pefloxacin, ciprofloxacin, ofloxacin

14C macrolides: erythromycin, klarithromycin, roxirthromycin, dirithromycin CYP3A4 chinolony rifampicin 14C macrolides imidazoly: ketokonazol, itrakonazol, flukonazol

Interaction with theofylin increase of

theofylin Cmax and AUC

(%) Linezolid

• Oxazolidinon – proteosyntetic inhibitor (binds on 23s subunit 50s – prevents 70s complex necessary for translation

• Bioavailability p.o. – 100%

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