Rifabutin and azithromycin seem not to affect serum levels ofeach other, but a very high incidence of neutropenia was seen inone study of combination. Both rifabutin and rifampicinmarkedly reduce serum levels of clarithromycin. Clarithromycin increases serum levels of rifabutin and combinationis associated with an increased risk of uveitis and neutropenia. Rifampicin (rifampin) greatly reduces telithromycin levels and concurrent use is not recommended.
Neutropenia. A study in 12 healthy subjects was designed to investigate safety and possible interactions between rifabutin 300mg daily, and azithromycin 250mg daily or clarithromycin 500mg twice daily, for a course of 14 days. The subjects were matched against 18 healthy controls who received either of macrolides or rifabutin alone. The study had to be abandoned after 10 days because 14 patients developed neutropenia; 2 taking rifabutin alone,and all 12 of those taking rifabutin with a macrolide. Eight subjects developed a fever,5 required colony simulating factors, and 3 required hospitalisation (See reference number 1).
Pharmacokinetics. In a study(See reference number 2) investigating a possible regimen for prophylaxis of Mycobacterium avium complex (MAC) disease, 12 HIV-positive patients were treated with clarithromycin 500mg daily, to which rifabutin 300mg daily was added on day 15. By day 42 clarithromycin AUC had fallen by 44%, and levels of metabolite, 14-hydroxyclarithromycin, had risen by 57%. A related study(See reference number 2) in 14 patients given clarithromycin 500 mg every 12 hrs and rifabutin 300mg daily found that after 28 days AUC of rifabutin had increased by 99%, and AUC of active metabolite, 25-O-desacetyl-rifabutin, had increased by 375%. Another group of patients with lung disease due to MAC were treated with clarithromycin 500mg twice daily. When rifabutin 600mg was added clarithromycin levels fell by 63 % (from 5.4 to 2 micrograms/mL) (See reference number 3). Limited information from a randomised study in healthy subjects found similar results (See reference number 1,4). Fluconazole appears to further increase effects of clarithromycin on rifabutin (See reference number 4). One study suggests that there is no pharmacokinetic interaction between azithromycin and rifabutin (See reference number 1).
Uveitis or arthralgias. Uveitis,and in some cases pseudojaundice, aphthous stomatitis and an arthralgia syndrome have been described in patients treated with both clarithromycin 1 to 2 g daily and rifabutin 300 to 600mg daily (See reference number 5-8). The presence of fluconazole does not appear to affect development of uveitis in patients taking clarithromycin with rifabutin,(See reference number 6,7,9)but it has been suggested that this was because only small doses (50 mg) were used (See reference number 7). Reports suggest that uveitis develops between 27 to 370 days after taking combination (See reference number 6,7). The reaction appears to be dose-dependent. In patients taking rifabutin 600mg with clarithromycin incidence of uveitis was 14 % in patients weighing more than 65 kg, 45 % in those weighing between 55 and 65 kg and 64 % in those weighing less than 55 kg. The risk of developing uveitis was reduced from a mean of 43 % to 13 % when dose of rifabutin was reduced to 300mg daily (See reference number 9). Uveitis did not develop in 8 patients taking rifabutin and azithromycin 500 mg daily,(See reference number 7)although cases of uveitis have been reported in patients taking rifabutin,fluconazole, and azithromycin 1.2 g weekly but they have been attributed to an interaction between rifabutin and fluconazole (See reference number 10). See Azoles + Rifabutin interaction.
Patients with lung disease due to MAC were treated with clarithromycin 500 mg twice daily. When rifampicin 600mg daily was added, mean serum levels of clarithromycin fell by almost 90 % (from 5.4 to
The manufacturer notes that rifampicin reduces AUC and maximum
serum levels of telithromycin by 86 % and 79%,respectively (See reference number 12). Two cases of cholestatic jaundice have been reported in patients taking
Both rifabutin and rifampicin are known enzyme inducers, which can increase metabolism of other drugs by liver, thereby reducing their serum levels. Rifampicin is recognised as being more potent inducer. Rifabutin is also a substrate for cytochrome P450 isoenzyme CYP3A4. Both clarithromycin and fluconazole are inhibitors of CYP3A4 and it is probable that clarithromycin and fluconazole exert additive effects resulting in greater inhibition of rifabutin metabolism than occurs with either drug alone (See reference number 4).
The reason for uveitis is not known, but based on animal studies it has been suggested that it is associated with effective treatment of MAC and is due to release of a mycobacterial protein, rather than a toxic effect of drugs (See reference number 15). It has been suggested that lower body weight and concurrent clarithromycin may result in toxic rifabutin serum levels,although concurrent fluconazole which increases levels does not appear to be a fac
Direct information appears to be limited to reports cited but interactions would appear to be established. What is not entirely clear is whether these interactions result in treatment failures because of potentially subtherapeutic clarithromycin serum levels. Because of lack of information, be alert for evidence of reduced efficacy if clarithromycin and rifampicin are used.
Although rifabutin can lower clarithromycin levels, efficacy of this combination for MAC infection is established, although not without risk, see Uveitis, below. Clarithromycin raises rifabutin levels and therefore increases risks of adverse effects. Concurrent use may therefore be desirable,but monitoring for adverse effects is necessary.
Due to a pharmacokinetic interaction UK manufacturers recommend that telithromycin should not be given during and for 2 weeks after use of rifampicin (See reference number 12)
Information regarding neutropenia with macrolides and rifamycins is very limited but what is known suggests that white cell counts should be monitored closely if rifabutin is given with azithromycin or clarithromycin. Rifabutin is known to cause polyarthritis on rare occasions,but in conjunction with clarithromycin it appears to happen at much lower doses (See reference number 8). Careful monitoring is necessary.
The CSM in UK has warned about need to be aware of increased risk of uveitis with clarithromycin and rifabutin(See reference number 16) and of raised rifabutin levels. If uveitis occurs CSM recommends that rifabutin should be stopped and patient should be referred to an ophthalmologist (See reference number 16). Because of increased risk of uveitis they also say that consideration should be given to reducing dosage of rifabutin to 300mg daily in presence of macrolides (See reference number 16)
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