Towards an European consensus indications for Towards an European - - PowerPoint PPT Presentation

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 Safety of macrolides macrolides : where are the limits for the : where are the limits for the indications and to which patients do they apply ? indications and to which patients do they apply ?

(B. (B. Schlemmer Schlemmer, Paris, F) , Paris, F)

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 Are there any safety issues regarding macrolides macrolides ? ? Are there any drug interactions which preclude the use of Are there any drug interactions which preclude the use of macrolides macrolides in in 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 Safety of macrolides macrolides

• 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 Side-effects of macrolides macrolides

• How do

How do macrolides macrolides behave regarding the behave regarding the impact of antibiotics impact of antibiotics

• n endogenous flora
• n endogenous flora ? To be discussed with microbiologists…

? To be discussed with microbiologists…

• GI tract side effects most prevalent, with an interest for new

GI tract side effects most prevalent, with an interest for new compounds compounds vs vs erythromycin erythromycin

• Allergy : rare

Allergy : rare

• Hepatic abnormalities : increase in liver enzymes usually

Hepatic abnormalities : increase in liver enzymes usually asymptomatic asymptomatic, , cholestasis cholestasis very rare very rare

• Headache, dizziness…

Headache, dizziness… Globally : a well tolerated class of antibiotics Globally : a well tolerated class of antibiotics Most side-effects = only “ Most side-effects = only “unconfortable unconfortable” !! ” !! Do they induce poor compliance ? Do they induce poor compliance ?

Drug interactions with Drug interactions with macrolides macrolides

• The main problem due to interactions between some

The main problem due to interactions between some macrolides macrolides and the and the cytochrome cytochrome P 450 system, especially the CYP3A subclass of enzymes P 450 system, especially the CYP3A subclass of enzymes

• 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 ++ ++ + + ND ND 0/+ 0 0/+ 0 ciclosporin ciclosporin ND ND ND ND ND ND +++ +++ +++ +++ +++ +++ + + carbamazepin carbamazepin ND ND 0/+ 0/+ ND ND +++ +++ + + + + 0/+ 0/+ 0/+ 0/+ midazolam midazolam ++ ++ ND ND ++ ++ ND ND ND ND + + ND ND warfarin warfarin ND ND ND ND + + ND ND ND ND ND ND terfenadin terfenadin ++ ++ ND ND +++ +++ 0/+ 0/+ ND ND ND ND cisapride cisapride ND ND ++ ++ ND ND ++ ++ ++ ++ ND ND ND ND ______________________________________________________________________________ ______________________________________________________________________________ From From Petitjean 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 for spira spira and the new and the new macrolides macrolides

Clinical meaningfulness of safety concerns and drug Clinical meaningfulness of safety concerns and drug interactions of interactions of macrolides macrolides

• 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 :

• ther current medications
• ther current medications
• underlying disease (cardiac, pulmonary, hepatic…)

underlying disease (cardiac, pulmonary, hepatic…)

• What is the actual need for

What is the actual need for macrolides macrolides for each specific indication ? for each specific indication ?

Safety, medical needs and alternative therapies Safety, medical needs and alternative therapies

Differenciation Differenciation between between “indications” “indications” and and “optimal choice”… “optimal choice”… Where is “optimal choice” for Where is “optimal choice” for macrolides macrolides ? ?

• In the case of

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

– – Legionella Legionella infection or “atypical pneumonia” (empiric therapy) infection or “atypical pneumonia” (empiric therapy) – – STDs STDs ?… ?…

• In the case of improvement of patient’s

In the case of improvement of patient’s comfort and compliance comfort and compliance

– – example : single 1g example : single 1g azithro azithro for for chlamydial urethritis chlamydial urethritis/ /cervicitis cervicitis

• Elsewhere :

Elsewhere : macrolides macrolides only considered as an

• nly considered as an option
• ption 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 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 therapy therapy or

• r merely

merely a a therapeutic therapeutic option ?

• ption ?

= a = a risk risk/ /benefit benefit issue ? issue ?

• Yes

Yes, but , but only

• nly for rare situations in

for rare situations in selected selected « « at risk at risk » patients » patients

• In

In most most instances instances safety safety would would not not be be considered considered as a as a problem problem

– – healthy adults healthy adults – – mild side mild side-

• effects

effects – – unpredictable unpredictable... ...

• In addition

In addition should be discussed with should be discussed with regard to regard to side side-

• effects

effects of

• f other antibiotic
• ther antibiotic

classes : classes : is is the GI the GI tolerance tolerance of

• f co

co-

• amoxiclav better

amoxiclav better ?... ?...

Conclusion : a check- Conclusion : a check-list list for for any antibiotic any antibiotic class class

• Types of

Types of side side-

• effects

effects or

• r drug

drug IA IA vs pts vs pts populations populations

• frequency

frequency

• risk

risk

• severity

severity

• Medical need

Medical need of the

• f the antibiotic

antibiotic in in each each type of indication type of indication

• best

best choice choice ? ?

• or
• r only
• nly one of
• ne of different

different therapeutic therapeutic options ?

• ptions ?
• Safety

Safety of alternative

• f alternative therapies

therapies