European conference on antibiotic use in Europe, Brussels, BE, Nov. 15-17, 2001 European conference on antibiotic use in Europe, Brussels, BE, Nov. 15-17, 2001 Workshop 6 Workshop 6 Towards an European consensus indications for Towards an European consensus indications for major antibiotic classes : an exercise with the major antibiotic classes : an exercise with the macrolides macrolides Safety of macrolides macrolides : where are the limits for the : where are the limits for the Safety of indications and to which patients do they apply ? indications and to which patients do they apply ? (B. Schlemmer Schlemmer, Paris, F) , Paris, F) (B. Trying to find a matrix for any other antibiotic class... Trying to find a matrix for any other antibiotic class... Are there any safety issues regarding macrolides macrolides ? ? Are there any safety issues regarding Are there any drug interactions which preclude the use of macrolides macrolides in in Are there any drug interactions which preclude the use of some people ? some people ? If limits for use have to be pointed out, to which patients do they apply ? If limits for use have to be pointed out, to which patients do they apply ?
Safety of macrolides macrolides Safety of Should resistance (or poor intrinsic antibacterial Should resistance (or poor intrinsic antibacterial • • activity) and consequent therapeutic failure or activity) and consequent therapeutic failure or emergence of resistance during therapy be considered emergence of resistance during therapy be considered as a safety issue … ? as a safety issue … ? To be discussed elsewhere To be discussed elsewhere Apart from this problem… Apart from this problem… • • – Macrolides Macrolides usually considered as well-tolerated antibiotics usually considered as well-tolerated antibiotics – – Side effects : Side effects : frequent frequent – but usually mild to moderate but usually mild to moderate
Side-effects of macrolides macrolides Side-effects of How do macrolides macrolides behave regarding the behave regarding the impact of antibiotics impact of antibiotics How do • • on endogenous flora ? To be discussed with microbiologists… ? To be discussed with microbiologists… on endogenous flora GI tract side effects most prevalent, with an interest for new GI tract side effects most prevalent, with an interest for new • • compounds vs vs erythromycin erythromycin compounds Allergy : rare Allergy : rare • • Hepatic abnormalities : increase in liver enzymes usually Hepatic abnormalities : increase in liver enzymes usually • • asymptomatic, , cholestasis cholestasis very rare very rare asymptomatic Headache, dizziness… Headache, dizziness… • • Globally : a well tolerated class of antibiotics Globally : a well tolerated class of antibiotics Most side-effects = only “unconfortable unconfortable” !! ” !! Most side-effects = only “ Do they induce poor compliance ? Do they induce poor compliance ?
Drug interactions with macrolides macrolides Drug interactions with The main problem due to interactions between some macrolides macrolides and the and the The main problem due to interactions between some • • cytochrome P 450 system, especially the CYP3A subclass of enzymes P 450 system, especially the CYP3A subclass of enzymes cytochrome Finally results in lowered metabolism of CYP3A-dependent drugs Finally results in lowered metabolism of CYP3A-dependent drugs • • ______________________________________________________________________ ______________________________________________________________________ drug drug azi azi clari clari diri diri ery ery josa josa mid mid roxi roxi spira spira ______________________________________________________________________________ ______________________________________________________________________________ théophyllin théophyllin 0 0 0 0 0 0 ++ ++ + + ND ND 0/+ 0 0/+ 0 ciclosporin ciclosporin ND ND ND ND ND ND +++ +++ +++ +++ +++ +++ + + 0 0 carbamazepin carbamazepin ND ND 0/+ 0/+ ND ND +++ +++ + + + + 0/+ 0/+ 0/+ 0/+ midazolam midazolam 0 0 ++ ++ ND ND ++ ++ ND ND ND ND + + ND ND warfarin warfarin 0 0 ND ND ND ND + + ND ND ND ND 0 0 ND ND terfenadin terfenadin 0 0 ++ ++ ND ND +++ +++ 0/+ 0/+ ND ND 0 0 ND ND cisapride cisapride ND ND ++ ++ ND ND ++ ++ ++ ++ ND ND ND ND 0 0 ______________________________________________________________________________ ______________________________________________________________________________ From Petitjean From Petitjean et al. et al. ND=undocumented ND=undocumented Mainly considered as a class-effect, resulting from what is known for erythromycin, except Mainly considered as a class-effect, resulting from what is known for erythromycin, except for spira spira and the new and the new macrolides macrolides for
Clinical meaningfulness of safety concerns and drug Clinical meaningfulness of safety concerns and drug interactions of macrolides macrolides interactions of Usually no problems for healthy adults being treated for mild to moderate Usually no problems for healthy adults being treated for mild to moderate • • infections infections Relation between drug intolerance (GI side-effects) and compliance: a Relation between drug intolerance (GI side-effects) and compliance: a • • poorly documented issue poorly documented issue – relation between duration of therapy and side-effects relation between duration of therapy and side-effects – – are shorter regimens (5 days are shorter regimens (5 days vs vs 8-10d, or 3 days 8-10d, or 3 days vs vs 5d) better tolerated ? 5d) better tolerated ? – Most problems, if any, raising from elderly patients with : Most problems, if any, raising from elderly patients with : • • other current medications other current medications • • underlying disease (cardiac, pulmonary, hepatic…) underlying disease (cardiac, pulmonary, hepatic…) • • What is the actual need for macrolides What is the actual need for macrolides for each specific indication ? for each specific indication ? • •
Safety, medical needs and alternative therapies Safety, medical needs and alternative therapies Differenciation between between “indications” “indications” and and “optimal choice”… “optimal choice”… Differenciation Where is “optimal choice” for macrolides macrolides ? ? Where is “optimal choice” for In the case of allergy allergy (especially allergy to (especially allergy to betalactams betalactams) ) In the case of • • In the case of specific indications specific indications for this class of antibiotics for this class of antibiotics In the case of • • – Legionella Legionella infection or “atypical pneumonia” (empiric therapy) infection or “atypical pneumonia” (empiric therapy) – – STDs STDs ?… ?… – In the case of improvement of patient’s comfort and compliance comfort and compliance In the case of improvement of patient’s • • – example : single 1g example : single 1g azithro azithro for for chlamydial urethritis chlamydial urethritis/ /cervicitis cervicitis – Elsewhere : macrolides Elsewhere : macrolides only considered as an only considered as an option option among other among other • • antibiotics antibiotics
SAFETY / DRUG INTERACTIONS AND LIMITS FOR SAFETY / DRUG INTERACTIONS AND LIMITS FOR THE USE OF MACROLIDES THE USE OF MACROLIDES To be discussed with be discussed with respect to the respect to the consideration given consideration given to macrolides : to macrolides : first first line line To therapy or or merely merely a a therapeutic therapeutic option ? option ? therapy = a risk risk/ /benefit benefit issue ? issue ? = a Yes, but Yes , but only only for rare situations in for rare situations in selected selected « « at risk at risk » patients » patients • • In most most instances instances safety safety would would not not be be considered considered as a as a problem problem In • • – healthy adults healthy adults – – mild side mild side- -effects effects – – unpredictable unpredictable... ... – In addition should be discussed with should be discussed with regard to regard to side side- -effects effects of of other antibiotic other antibiotic In addition • • classes : is is the GI the GI tolerance tolerance of of co co- -amoxiclav better amoxiclav better ?... ?... classes :
Conclusion : a check-list list for for any antibiotic any antibiotic class class Conclusion : a check- Types of side side- -effects effects or or drug drug IA IA vs pts vs pts populations populations Types of • • • frequency frequency • • risk risk • • severity severity • Medical need of the of the antibiotic antibiotic in in each each type of indication type of indication Medical need • • • best best choice choice ? ? • • or or only only one of one of different different therapeutic therapeutic options ? options ? • Safety of alternative of alternative therapies therapies Safety • •
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