Special populations. 11:30-11:40 Special populations (AIDS, etc...) Y. Van Laethem (Brussels)

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1 Special populations 11:30-11:40 Special populations (AIDS, etc...) Y. Van Laethem (Brussels)

2 High persistant concentration in monocytes/polymorphonuclear leucocytes of : - azithromycin and clarithromycin Bui et al AAC 1999 : 43 (9) azithromycin, with AIDS patients healthy volunteers Nabb et al Int J. Ant Agents (1) 37

3 Mycobacterium avium complex (MAC) (1) Incidence of disseminated MAC infection : 15%-40% in advanced HIV infection (<50 CD4/mm³) Masur et al NEJM 1993:329:898 However, dramatic decrease of all OI since the HAART (mid 97) 21.9/100 person-year in /100 person-year in 97 Pallela et al NEJM 1998:338:853

4 Mycobacterium avium complex (MAC) (2) Activity of neomacrolides on MAC - in vitro : Casal (Chemotherapy 87) - animal model : Fernandes 89 - in vivo: Clarithromycin Dautzenberg ARRD. 91 Azithromycin Young Lancet 91

5 Mycobacterium avium complex (MAC) (3) Several RDB studies have shown : Clarithromycin - Monotherapy (0.5-2g/d) * Clinical improvement * negative BC by 4-8 weeks BUT appearance of R after +/- 4 months (> 20%) Chaisson et al (Ann. Intern. Med 1994:121:905

6 Mycobacterium avium complex (MAC) (4) Clarithromycin - in association with 1) Ethambutol : * decrease in resistant strains * few additional side effects 2) Ethambutol + Rifabutin * same results * trend to lower emergence of BUT poorly tolerated drug interactions Havlir et al NEJM 1996: 335:392 Gordin et al CID 1999 : 28 : 1080 Benson et al JID 2000 : 181: 1289

7 Mycobacterium avium complex (MAC) (5) Clarithromycin 500 mg BID showed lower mortality than 1000 mg BID Cohn et al CID :125 Azithromycin - Monotherapy Dose ranging (88 patients) 600 mg/d mg/d BC (-) : 54% Clinical improvement BUT GI side effects 1200 >> 600 Koletar et al AAC 1999 :43 : 2869

8 Mycobacterium avium complex (MAC) (6) Azithromycin/Clarithromycin - in association with ethambutol 24 weeks RDB study (246 patients) 1) + clarithro 500 mg BID 2) + azithro 250 mg/d 3) + azithro 600 mg/d 1) ans 3) : same clinical/ BC results Dunne et al CID 2000 : 31 : 1245

9 MAC primary prophylaxis (1) Azithro once a week (1200 mg) RDB study : Azi> placebo Oldfield et al CID 1998 Clarithro BID (500mg) RDB study Placebo Clari BC+ 16% 6% Pierce et al NEJM 1996:335:384

10 MAC primary prophylaxis (2) In association : RDB patients Rifabutin Clari Clari+ Rifa BC(+) 15% 9% 7% RR / 44% 57% 29% 27% S.E Benson et al JID 2000:181:1289

11 Discontinuation MAC prophylaxis No BC (+) and/or clinical related event If patients > 100 CD4 /mm³ > 3-6 months ANN. INT. MED 2000:133:493 NEJM 2000:342:1085

12 Toxoplasmic encephalitis (1) In vitro : inhibition rather than killing Aranjo et al AAC 1988 : 32:755 Huskinson et al JID 1991 : 164 : 170 Animal models ( mice) : Clarithomycin + pyrimethamine or + minocycline = sulfamethoxazole + pyrimethamine - Derouin et al AAC 1992 : 36 : Hutch et al J AIDS 1994: 7 (11) :1141

13 Toxoplasmic encephalitis (2) In vivo : - pilot study in 13 patients pyrimethamine + clarithomycin = pyrimethamine + clindamycin Fernandez - Martin AAC 1991 : 35 (10) Clarithromycin (1-2g/d) + minocyclin as salvage therapy 8 patients «Favorable» in acute/maintenance Lacassin et al AAC 1995 : 39 : 1 : Azithromycin mg/d (dose finding study) + pyrimethamine 30 evaluable patients - Induction : alternative/second line if intolerant of other drugs (2/3 response) ( mg/d) - Maintenance : 30 evaluable patients (+/- 50% relapse) Jacobson et al AIDS (5) 583

14 Bacillary angiomatosis (BA) and peliosis Neovascular proliferation due to Bartonella henselae or quintana Low prevalance : Germany 1.2/10³ HIV patients Plettenberg et al Dermatology 2000 : 201 (4) 326 Skin involvment most frequent (BA) +/- systemic infection : lymph nodes, liver, bone, Treatment with (neo)macrolides ( or tetracycline) > 8-12 weeks +/- chronic suppressive therapy ( frequent relapse)

15 Cryptosporidium GI infection In vitro : «moderate» activity alone/in addition to other drugs Giacometti et al JAC 2000 (3) : 375 & (4) : 453 In vivo : No RDB study anecdotal reports /short series in addition to other drugs (paromomycin, nitazoxanide, )

16 PCP Sulphonamide + azithromycin is active against PCP in animals Patients receiving prophylaxis for PCP with cotrimoxazole and MAI with (1) azithromycin or (2) azithro + rifabutin or (3) rifabutin (1) and (2) had 45% risk of developping PCP than (3) (p=0.008) Dune et al Lancet 1999 : 354 (9182) 891

17 Meningococcal Meningitis Postexposure prophylaxis (1) EASY IN ADULTS ( NON PREGNANT) : Single dose : CIPROFLOXACIN (500 mg) OFLOXACIN (400mg) LESS EASY IN CHILDREN : RIFAMPICIN q 12h x 2 days PREGNANT WOMEN : CEFTRIAXONE 250 mg IM single dose

18 Meningococcal Meningitis Postexposure prophylaxis (2) One study - Pharingeal swabs in 500 nursing school students - If colonized : randomized azithromycin 500 mg single dose rifampicin 600 mg BID - 4 doses eradication 1 week 2 weeks Azi 93% 93% Rifam 95% 91% GIRGIS et al Ped Inf Dis J : 17 (9) 816

19 Prevention of bacterial endocarditis (1) For oral and dental procedures, azithromycin and clarithromycin are recommended in place of erythromycin in case of penicillin allergy. - Dajani et al American Heart Association : JAMA 1997 : 277 : 1794 Based on several animal models data as : - Single dose clarithromycin > clindamycin in a rat streptococcal model -Vermot et al AAC 1196 : 40 (3) : 809

20 Prevention of bacterial endocarditis (2) In a rabbit streptococcal model -Azithromycin or clarithromycin = amoxicillin or clindamycin Rouse et al AAC 1997 : 41 (8) : Azithromycin = ampicillin Tsitsika et al AAC 2000 : 44 (6) :1754