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10/02/2005FARM2146 1
10/02/2005FARM2146 2
The macrolide family ...The macrolide family ...
erythromycin• roxithromycin• clarithromycin• dirithromycin
josamycinspiramycinmiocamycin
azithromycin
• telithromycin
10/02/2005FARM2146 3
Erythromycin: Erythromycin: activityactivity
Erythromycin A : mostly Gram (+) organisms
Plus:• Legionella p.• Chlamydia spp.• Mycoplasma spp.• Mycobacterium avium
10/02/2005FARM2146 4
Erythromycin - MIC distributions of isolates that lack resistance mechanisms
Mg/L .004 .008 .016 .032 .064 .125 .25 .5 1 2 4 8 16 32 >64S.aureus n n n nCoag-neg staph n n nS.saprophyticus n n nStreptococcus_A n n nStreptococcus_B n n nPneumococci n n nStrept misc n n n nEnterococcus n n n n nListeria n n nCorynebacteria n n nBacillus spp n n nH.influenzae n n n n n ASTM.catarrhalis n n nB.pertussis n n n nP.multocida n n nL. pneumophila n n n nCamp. jejuni n n nN.gonorrhoeae n n n nN.meningitidis n n n nM.pneumoniae n n n nBorr. burgdorferi n n nSRGA and SRGA- M, 1998-04-13, 2001-11-11G Kahlmeter & B.Olsson-Liljequist
++
10/02/2005FARM2146 5
Erythromycin: the Erythromycin: the problemsproblems
Instability in acid mediaErythromycin A14 atoms
Keto in C9
Alcohol in C6
10/02/2005FARM2146 6
O
O
H3C
OH
OH
OH
CH3
H3CH2C O
O
CH3
CH3
H3C
O
O
OHO
(H3C)2N
CH3
OH
H3C
CH3H3CO
H3C
O
O
H3C
OH
OH
CH3
H3CH2C O
O
CH3
C
H3C
O
O
OHO
(H3C)2N
CH3
OH
H3C
CH3H3CO
H3C
O
CH3
H3CH2C O
O
CH3
H3C
O
O
OHO
(H3C)2N
CH3
OH
CH3H3CO
H3C
9
ERYTHROMYCIN
1
1
1
CH3
O OH3C
HO
CH3
8,9-anhydroerythromyin-6,9-hemiketal
erythromyin-6,9;9-12-spiroketal
Ery
thro
myc
in:
Ery
thro
myc
in: d
etai
ls o
f de
tails
of
acid
the
degr
adat
ion
acid
the
degr
adat
ion
10/02/2005FARM2146 7
What have the chemists done to What have the chemists done to avoid acidavoid acid--instability ?instability ?
6-methoxy
9-N-oxime
9-amino
9-CH2, 9a-aza
10/02/2005FARM2146 8
What have the chemists done to What have the chemists done to avoid acidavoid acid--instability ?instability ?
azithromycin15 atoms
9-CH2, 9a-aza
Erythromycin A
dirithromycin
roxithromycin9-N-oxime
erythromycylamine9-amino
clarithromycin6-methoxy
acid stability
10/02/2005FARM2146 9
Did these modifications change Did these modifications change anything anything else in PKelse in PK ??
clarithromycinhigher tissue accumulation
roxithromycin
dirithromycinmuch
higher tissue accumulation
dibasicazithromycin
pharmacokinetic differentiation
10/02/2005FARM2146 10
Did these modifications change Did these modifications change anything else ?anything else ?
Cytochrome P450 interactions
clarithromycinroxithromycin
dirithromycin
azithromycin
erythromycin A + + + + + +
10/02/2005FARM2146 11
Drug interactions with Drug interactions with macrolidesmacrolides
• The main problem due to interactions between some macrolides and the cytochrome P 450 system, especially the CYP3A subclass of enzymes
• Finally results in lowered metabolism of CYP3A-dependent drugs______________________________________________________________________drug azi clari diri ery josa mid roxi spira______________________________________________________________________________théophyllin 0 0 0 ++ + ND 0/+ 0ciclosporin ND ND ND +++ +++ +++ + 0carbamazepin ND 0/+ ND +++ + + 0/+ 0/+midazolam 0 ++ ND ++ ND ND + NDwarfarin 0 ND ND + ND ND 0 NDterfenadin 0 ++ ND +++ 0/+ ND 0 NDcisapride ND ++ ND ++ ++ ND ND 0______________________________________________________________________________From Petitjean et al.
N=undocumentedMainly considered as a class-effect, resulting from what is known for erythromycin, except
for spira and azithromycin
10/02/2005FARM2146 12
Basic indications of (classical) macrolides Basic indications of (classical) macrolides in a world of no resistancein a world of no resistance
erythromycin
clarithromycin
roxithromycin
dirithromycin
azithromycin
Respiratory tract infections• pharyngitis• otitis• sinusitis• acute exacerbations of chronic
bronchitis• community acquired pneumonia• legionellosis• C. pneumoniae• Mycobacterium avium (AIDS)
Genital/Ocular infections• chlamydiosis (C. trachomatis)• syphilis• donovanosis• gonorhhea
Gastric ulcer (H. pylori)
10/02/2005FARM2146 13
Which (who ...) is the best ?Which (who ...) is the best ?
erythromycin
clarithromycin
roxithromycin
dirithromycin
azithromycin
10/02/2005FARM2146 14
But was has been the problem ?But was has been the problem ?
Emergence of resistance
Target modification: erm
Efflux: Mef
erythromycin
clarithromycin
roxithromycin
dirithromycin
azithromycin
All are similarly affected
10/02/2005FARM2146 15
Mechanisms of macrolide resistance
• Ribosomal modification by methylase (erm genes)– S. pneumoniae: erm(B) 75-100% of Ery-R strains in Europe– S. pyogenes: erm(B) generally <50% of Ery-R strains
erm(A)
• Ribosomal modification by mutation (rRNA, proteins)– Occasional in Ery-R S. pneumoniae– Rare in Ery-R S. pyogenes (up to 18% in Eastern Europe)– The only mechanism or highly prevalent in H. pylori,
Campylobacter, M. avium
• Drug efflux (mef genes)– <25% in Ery-R S. pneumoniae– >50% in Ery-R S. pyogenes (up to 95%)
10/02/2005FARM2146 16
Correlation between erythromycin MICs andresistance mechanisms
0
10
20
30
40
50
No.
of s
train
s
0.01
0.02
0.03
0.06
0.12
0.25 0.5 1 2 4 8 16 32 64 >64
Erythromycin MIC (ug/ml)
mefE+ermB
ermB
mefE
none
Nagai ICAAC 2000, abstr # 892
10/02/2005FARM2146 17
The Alexander Project 1999:S. pneumoniae, Macrolide Resistance
Brazil 4.0%
Mexico22%
USA33%
South Africa13%
Saudi Arabia 18%
Hong Kong82%
Israel23%
Japan78%
Singapore55%
Kenya0.5%
Russia7%
Europe20%
Resistance defined as erythromycin MIC ≥1mg/L
10/02/2005FARM2146 18
Distribution of erythromycin-resistance phenotypesamong pneumococci from 8 different European
countries (1998-2000)
distribution of resistance phenotype Country
(total N of isolates)
ref
overall % of
erythromycin-resistance MLSB M other
Belgium (59)
Finland (651)
France (48)
Germany (102)
Greece (140)
Italy (85)
Norway (8)
Spain (109)
1
2
3
4
5
6
7
8
31
11.2
53
10.6
18
31.7
4.5
36.1
91.5
71
100
74
67.9
76.5
75
84
8.5
21
0
22.5
29.2
23.5
25
15
0
11.2
0
3.5
3.6
0
0
1
10/02/2005FARM2146 19
Resistance to macrolides in Greece
05
101520253035
95-96
96-97
97-98
98-99
99-00S. pneumoniaeS. pyogenes
• Bronchitis• pneumonia• sinusitis• otitis
• Pharyngitis
10/02/2005FARM2146 20
Inhibition of Protein Synthesis (1)Inhibition of Protein Synthesis (1)
• Inhibition of peptidyl transferase activity
Domain V5S rRNA30S
50S
Domain II
Pocket: peptidyl transferase site
V
II
Erythromycin A2058
752
5S rRNAOO
O
-cladinose
ermmef
Modified from Bryskier(FDA presentation of KETEK®)
10/02/2005FARM2146 21
TelithromycinTelithromycin
10/02/2005FARM2146 22
Resistance: a semiResistance: a semi--rational answer ...rational answer ...
erythromycin A lateral basichydrophobic
chain to increase activity
telithromycin
C6-methoxyfor acid-stabilityketolides
C3-descladinose
Target modification: ermA
Efflux: Mef E
10/02/2005FARM2146 23
Inhibition of Protein Synthesis (2)Inhibition of Protein Synthesis (2)
• Inhibition of peptidyl transferase activity
Domain V5S rRNA
Domain II
Pocket: peptidyl transferase site
5S rRNA5S rRNA
2058
752
V
II
V
II
Erythromycin A Telithromycin2058
752
30S
50S
O O
O
OO
O
-cladinose
erm
From Bryskier,FDA presentation of KETEK®
mef
10/02/2005FARM2146 24
MICMIC5050 [µg/ml] of wild [µg/ml] of wild type type and and mutant strainsmutant strains
Erythromycin Telithromycin
S. pyogenes (WT)(ermTR ind.)(ermTR const.)(ermB ind.) (ermB const.) (mef)
0.034
>64>64>64
8
0,080,060,25
0,5 - 18
0,5
S. pneumoniae (WT)(ermB const.)(mef)
0,03>64
2
0,0080,06
0,125
10/02/2005FARM2146 25
TelithromycinTelithromycin
• Telithromycin, the first ketolide, was designed to overcome erythromycin A resistance within Gram (+) positive cocci and take advantage of PK improvements of clarithromycin
O
O
O
OOCH3
O
9
6N
R
3
OO D - desosamine
New chemical class (3–keto)
active against ermR
C11–C12 carbamatefor anchoring
11
12
To avoid chemicalinstability
Side chain for improvedactivity
10/02/2005FARM2146 26
Pharmacokinetics of telithromycin (as submitted to the FDA; april 2001)
800 mg 800 mg(single dose) (7 days)
Cmax (mg/L) 1.9 (42) 2.3 (31)
C24h (mg/L) 0.03 (45) 0.07 (72)
AUC24h (mgxh/L) 8.3 (31) 12.5 (43)
t 1/2 (h) 7.2 (39) 9.8 (20)
The company has declared that activity of telithromycin is driven by Cmax/MIC and by AUC24h/MIC ratios
http://www.fda.gov/ohrms/dockets/ac/01/slides/3746s_09_aventis/
10/02/2005FARM2146 27
Pharmacodynamics of telithromycin (as based on FDA submission; april 2001)
http://www.fda.gov/ohrms/dockets/ac/01/slides/3746s_09_aventis/
Organism MIC90
S. pneumoniae < 0.008 - 0.25S. pyogenes < 0.015 - 0.06H. influenzae 2.0 - 4.0M. catarrhalis 0.12L. pneumophila 0.03 - 0.12C. pneumoniae 0.03 - 2M. pneumoniae 0.25
Cmax/MIC90max AUC24h/MIC90max
7.6 33.231.6 1380.475 2.075
15.8 69.1
Activity will be good for MIC≤ 0.25 mg/L, but may become problematic for higher MICs
10/02/2005FARM2146 28
Which are the sensivities of S. pneumoniae towards telithromycin in Belgium in 2000 ?
0
20
40
60
80
100
0.015 0.03 0.06 0.12 0.25 0.5 1 2
Ery-S
MIC (mg/L)
% o
f stra
ins PK/PD limit of sensitivity (0.25 mg/L)
Ery-r
But MIC90 for Ery-r strains: 0.25-0.5 ...MIC90 for Ery-s strains: < 0.06 ...
Verhaegen & Verbist, Acta Clin. Belg. 2001, 56: 351
10/02/2005FARM2146 29
MacrolidesMacrolides: the 16 atoms family: the 16 atoms family
Instability in acid mediaErythromycin A14 atoms
Carbomycin A / Spiramycins16 atoms
Intrinsicallyacid-stables
10/02/2005FARM2146 30
MacrolidesMacrolides: the 16 atoms family: the 16 atoms family
10/02/2005FARM2146 31
Properties of the 16 atoms familyProperties of the 16 atoms family
Low cyt P450interactionsspiramycin
Non ermB inducers
Non mefE substrates
josamycin
miocamycin
Carbomycin A / Spiramycins 16 atoms But, usually, lower
intrinsic activities
Intrinsicallyacid-stables
10/02/2005FARM2146 32
MacrolidesMacrolides: the present family picture: the present family picture
Erythromycin A
clarithromycin
roxithromycin
dirithromycin
azithromycin
PK
spiramycin
josamycin
miokamycin
mef
telithromycin ?erm
mef