1. health and fitness
2. disease

S37
Rifabutin Therapy for Disseminated Mycobacterium avium Complex Infection
Paul M. Sullam
Department of Medicine, Veterans Affairs Medical Center,
and the University of California, San Francisco, California
Although numerous antimicrobial agents have been used to treat disseminated Mycobacterium
avium complex (MAC) infection, the optimal therapy for this disease is unknown. One potentially
effective agent is rifabutin, which has demonstrated activity against MAC both in vitro and in
animal models of infection. In clinical trials, cultures of blood from 46% to 92% of patients become
sterile after therapy with rifabutin combined with ethambutol, clofazimine, or amikacin. Moreover,
the efficacy of ethambutol combined with clofazimine is markedly enhanced by rifabutin. In combination with clarithromycin, rifabutin at dosages of ~450 mg/d has been associated with a high
incidence of uveitis, thus indicating that only 300 mg/d may be given with this macrolide. Although
a definitive role for rifabutin in the treatment of MAC infection has not been established, this agent
will likely be of value as an adjunct to macrolide-based therapy or in the treatment of macrolideintolerant patients.
Reprints or correspondence: Dr. Paul M. Sullam, Veterans Affairs Medical
Center (111 W), 4150 Clement Street, San Francisco, California 94121.
Clinical Infectious Diseases 1996;22(Suppll):S37-42
This article is in the public domain.
In Vitro Studies
Since the in vitro activity of rifabutin is addressed elsewhere
in this supplement, details of such data will not be discussed
at length here. In brief, several studies indicate that, as measured by MICs, rifabutin is active against MAC in vitro. Although MICs vary considerably between strains and with differing methodologies, MIC so values of 0.1 to 0.5 j.lg/mL are
typical, as are MIC 90 values of 0.5 to 4.0 j.lg/mL [13, 14].
Given that oral administration of rifabutin results in peak serum
concentrations of 0.4 to 0.6 j.lg/mL [15], 20%-32% of strains
have been classified as "susceptible;" another 57%-74% have
been deemed "moderately susceptible." Although the above
MICs are at best only minimally lower than the achievable
serum levels of this drug, concentrations of rifabutin within
macrophages are severalfold higher, possibly rendering this
agent more effective in killing intracellular organisms [16].
In addition to its intrinsic antimicrobial activity, synergy in
vitro between rifabutin and a variety of other agents (including
ethambutol and clarithromycin) has also been reported [17, 18],
further suggesting that rifabutin may be of value as therapy.
Numerous questions exist about the validity of in vitro assays
for antimycobacterial activity. These methods are not standardized, and results often vary under different experimental conditions. Notwithstanding these caveats, such data have provided
the rationale for subsequent testing in animal models of infection and in humans.
In Vivo StUdies
Additional evidence for the activity of rifabutin is provided
by animal models of disseminated MAC infection. In studies
by Gangadharam et a1. [19,20], beige mice infected with MAC
had little response to rifabutin alone. However, combinations
of rifabutin with clofazimine were more effective than the latter
drug alone in reducing titers of MAC organisms within the
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Mycobacterium avium complex (MAC) has long been recognized as a frequent cause of chronic pulmonary infection, especially in patients with underlying medical conditions such as
silicosis [1]. Until recently disseminated infection was rare;
only about three dozen cases were reported in the pre-AIDS
era [2]. In 1981, however, numerous centers began to observe
cases of MAC bacteremia and multiorgan involvement in patients with AIDS [3]. At first there was controversy as to
whether infection with this organism represented true disease
or merely colonization. Subsequent case-control studies have
demonstrated that patients with disseminated MAC infection
are more likely to be symptomatic with fever, chills, wasting,
and diarrhea. Moreover, disseminated MAC infection is associated with a 50% reduction in life expectancy [4-7] (figure 1).
In view of these findings, most authorities recommend antimicrobial therapy for all patients with disseminated MAC infection [8-10]. The agents proposed for therapeutic use include
macrolides, rifamycins, quinolones, clofazimine, ethambutol,
and amikacin. However, the optimal treatment of disseminated
MAC infection has not yet been clearly detennined. Most trials
have examined the efficacy of one or more multidrug regimens,
each typically containing three or four agents. As a result it is
difficult to quantify the contribution of any single drug in clearing infection. Although a few studies have assessed the efficacy
of monotherapy with individual antimicrobial agents [11,12],
thus providing some data on the relative efficacy, no such
infonnation exists for rifabutin. Despite these limitations, results from in vitro studies, animal models of infection and
clinical trials indicate that rifabutin may be of value as th~rapy
for disseminated MAC infection.
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Figure 1. Survival of patients with disseminated Mycobacterium
avium complex infection: untreated patients (dotted line) vs. treated
patients (solid line) (P < .0001). Data are from [4].
Clinical Studies
One of the earliest experiences with rifabutin as therapy for
MAC infection was reported by Masur et al. [27], who treated
patients with AIDS and MAC bacteremia with rifabutin (150
mg/d) and clofazimine, often in combination with amikacin.
Cultures of blood from six of 13 evaluable patients became
sterile. However, clinical improvement was noted in only one
case. In a subsequent study by Hoy et al. [28], cultures of
blood from 22 of 25 patients became sterile (mean time to
sterilization, 6.5 weeks) following therapy with rifabutin (300
mg/d) combined with isoniazid, ethambutol, and clofazimine.
Clinical improvement in several MAC-related sYmptoms and
Table 1. Response of patients with Mycobacterium avium complex
bacteremia to treatment with rifabutin or placebo in combination with
clofazimine and ethambutol.
No. of patients wtih microbiological
response/total no. of patients evaluated*
Week of
therapy
4
8
12
RBT/CLOIEMB
PLNCLOIEMB
P value
7/11
7/10
0/13
1/8
1/7
<.001
.025
.060
6/9
NOTE. RBT = rifabutin; CLO = c1ofazimine; EMB = ethambutol; PLA
= placebo. Reprinted with permission from [30].
* For all responders in both groups, blood cultures were sterile, except for
one patient receiving RBT/CLOIEMB (at week 4 a 2 loglo reduction in cfu/
mL of blood was noted).
Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014
spleens of mice [19]. Moreover, the activity of amikacin combined with clofazimine against organisms within lungs was
enhanced by the addition of rifabutin [20]. Using a model that
may be more representative of AIDS (mice with selective T
helper cell depletion), Furney et al. [21] have shown that rifabutin alone can induce clearance of MAC from the spleen and
liver. Saito et al. [22] (using black mice with disseminated
MAC infection) have reported similar findings. In addition to
its activity when given alone, rifabutin has synergistic activity
in vivo when combined with ethambutol or macrolides
[23-26].
As with the in vitro studies discussed above, results from
animal studies have not been wholly consistent. Because of
differences among strains of MAC used in these models (in
terms of both virulence and antimicrobial susceptibility), there
exists an enormous potential for experimental artifact. Other
variables include differences in susceptibility to MAC among
mice or rat species and, in some models, different methods of
producing immunosuppression. Nonetheless, in most of the
above-mentioned studies, the ability ofrifabutin to reduce titers
of MAC organisms within organs of infected animals indicates
that this agent may be of value in the treatment of humans.
signs was noted at 3 months. Similar results were observed by
Dautzenberg et al. [29], who used a regimen ofrifabutin (300600 mg/d), isoniazid (5 mg/[kg' dD, and clofazimine (100 mg/
d). Cultures of blood from 16 of23 patients for whom bacteriologic data were available became sterile by the third month
of treatment. However, of those 16 responders, four (25%)
eventually relapsed.
Although these studies indicate that regimens containing rifabutin may be effective in the treatment of disseminated MAC
infection, the relative contribution of rifabutin in reducing microbial titers cannot be determined since other agents were used
concurrently. However, the impact of rifabutin on therapeutic
response is addressed in a recent double-blind, placebo-controlled, randomized trial [30] that examined the efficacy of
ethambutol and c10fazimine combined with either rifabutin
(600 mg/d) or placebo as treatment of patients with AIDS and
MAC bacteremia. The primary endpoint was microbiological
response, defined as sterilization or at least a 2 10glO reduction
in cfu/mL of blood. By week 4 of treatment, seven of 11
patients in the rifabutin group were classified as responders,
as compared with none of 13 patients in the placebo group (P
< .001) (table 1). Similar results were seen at weeks 8 and 12
of treatment. Cultures of blood from all but one responder
became sterile. No significant differences were noted between
the two groups in terms of adverse effects.
Taken as a whole, the above-mentioned studies indicate that
rifabutin has activity against disseminated MAC infection in
humans and that rifabutin in combination with other agents
would prove effective as therapy for MAC infection. It should
be noted that the response rates noted above are better than
those reported for many non-macrolide-containing regimens
[31, 32]. However, trials with macrolides have shown even
greater efficacy. For example, Dautzenberg et al. [33] have
reported a 63%-98% rate of sterilization of cultures of blood
from patients receiving a clarithromycin-containing regimen.
Comparable response rates have also been noted by Chaisson
et al. [34] for c1arithromycin monotherapy and by Young et
cm
1996; 22 (Supp! 1)
Rifabutin Therapy for MAC Infection
al. [35] for azithromycin monotherapy. On the basis of such
data, the U.S. Public Health Service has recommended that all
patients with AIDS and disseminated MAC infection be treated
with macrolides (either clarithromycin or azithromycin),
usually in combination with ethambutol and possibly a third
agent [10].
Current Studies
is now a two-arm trial comparing 300 mg of rifabutin or placebo in combination with clarithromycin and ethambutol. Completion of enrollment is anticipated by the end of 1995.
Several other trials that include rifabutin for the treatment
of MAC infection are currently in progress or scheduled to
start. The Canadian HIV Trials Network Study 087174 is an
open-label, two-arm, prospective study comparing rifampin
(600 mg/d), ethambutol (15 mg/[kg· dD, ciprofloxacin (750 mg
bj.d.), and clofazimine (100 mg/d) with rifabutin (600 mg/d),
ethambutol (15 mg/[kg· dD, and clarithromycin (1 g bj.d.). The
two regimens will be assessed with respect to microbiological
response (defined as two or more sterile blood cultures at week
16 of therapy), clinical response, and survival. Because of the
cases of uveitis discussed above, the dose of rifabutin has been
reduced from 600 to 300 mg/d. Enrollment began in October
1992, with a goal of enrolling 200 patients by early 1995.
ACTG 223 is a three-arm, prospective study comparing clarithromycin (500 mg bj.d.) combined with ethambutol, rifabutin
(450 mg/d), or both. Patients will be randomized to one of the
above-mentioned regimens and monitored every 4 weeks for
clinical and microbiological responses. Patients with a significant reduction in titers will continue their treatment, while
those lacking such a response will be randomized to a salvage
regimen. Recruitment is scheduled to begin in 1995, with a
target number of 246 enrollees.
CPCRA 027 is a prospective, four-arm study comparing
clarithromycin (500 or 1,000 mg/d) and ethambutol combined
with either rifabutin (450 mg/d) or clofazimine. The endpoints
are microbiological response (defined as sterile blood cultures
after 2 months of therapy), clinical response, and survival. A
total of 400 patients will be enrolled over a period of 2 years
beginning in 1995.
Summary
Numerous studies, either in progress or planned, will help
define the role of rifabutin in the treatment of disseminated
MAC infection. Pending the results ofthese trials, several roles
may be postulated for this agent. First, rifabutin may be of value
as part of a macrolide-containing regimen as initial therapy for
MAC infection. When used in conjunction with macrolides,
rifabutin may either enhance the rate of clearance of MAC or
prevent the emergence of resistance. Clearly, the risk of uveitis
must be considered if rifabutin is to be used with macrolides.
However, rifabutin at dosages of 300 mg/d (or even 150 mg/
d) may result in a low (but still detectable [39D incidence of
uveitis while still contributing to the antimicrobial activity of
macrolide regimens. As an alternative approach, rifabutin could
be used during the initial 4-8 weeks of clarithromycin therapy,
with the goal of inducing a more rapid reduction in titers of
MAC organisms or a more prompt clinical improvement. Combination therapy of such limited duration may be associated
with a lower incidence of uveitis than has been observed with
more prolonged treatment.
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In view of these recommendations, most ongoing trials on
the treatment of MAC infection in North America have at least
one treatment arm containing a macrolide. Among the studies
examining the efficacy of rifabutin is Pharmacia 0250. This
double-blind, randomized, three-arm trial initially compared
two doses ofrifabutin (900 or 600 mg/d) or placebo combined
with clarithromycin (1,000 mg bj.d.) and ethambutol (15 mg/
[kg· dD. Enrollment began in April 1993 at about 40 centers
throughout the United States.
Two subsequent developments have necessitated modification of the protocol. In reviewing data on clarithromycin monotherapy for MAC infection, the Food and Drug Administration (FDA) noted an increased mortality rate among patients
receiving 1 g bj.d. Although no reason for this association was
apparent, the FDA recommended that the maximum dose be
reduced to 500 mg bj.d. for these patients [10]. In addition,
by late 1993 reports began to emerge of uveitis in patients
receiving therapy with rifabutin in combination with clarithromycin. The Canadian HIV Trials Network Study 087174 (discussed below) noted that 23 (39%) of 59 patients given 600
mg/d of rifabutin combined with 1 g of clarithromycin (plus
ethambutol) bj.d. had uveitis [36]. Concurrently, nine of the
65 patients in the Pharmacia 250 trial had uveitis (B. Wynne
[Pharmacia, Piscataway, NI], personal communication). Since
this study remains blinded, the precise incidence of uveitis in
each treatment arm cannot be determined. Estimates range from
13.8% (if cases were equally distributed among the three arms)
to 39.1 % (if all cases were in a single arm).
The possible mechanisms of this toxic effect are discussed
elsewhere in this supplement. It is likely, however, that the
pathogenesis of uveitis is related to the pharmacokinetic interaction of clarithromycin and rifabutin. By inhibiting the cytochrome P-450 pathway, clarithromycin reduces the metabolism
of rifabutin, thus resulting in increased serum and tissue concentrations [37, 38]. It is presumed that these high levels of
rifabutin are cytotoxic or promote inflammation, but the details
of this process remain undefined.
In view of these reports of uveitis, the protocol for the Pharmacia 0250 study was modified in December 1993. The dosage
of clarithromycin was reduced to 500 mg bj.d., and that of
rifabutin was reduced to either 450 or 300 mg/d. During the
subsequent 6 months, four additional cases of uveitis were
described in 102 new enrollees. On the basis of the recommendations of the Data Safety Monitoring Board for this study, the
450-mg treatment arm was discontinued. Thus, Pharmacia 0250
S39
S40
em
Sullam
Addendum
Several developments relating to current studies discussed in
this paper have recently occurred. Pharmacia 0250 has completed
enrollment of new patients; preliminary results are anticipated by
the end of 1996. Final data from the Canadian HIV Trials Network
Study 087174 were presented last fall, indicating that combination
therapy with rifabutin, clarithromycin, and ethambutol results in
higher rates of microbial clearance from the blood (67 [69%] of
97 patients) than does the four-drug regimen (29 [30%] of 90
patients) [41]. The response rate was dependent on the dosage of
rifabutin and was higher at 600 mg/d (79%) than at 300 mg/d
(58%). However, the higher dosage was frequently associated with
the development of uveitis (24 of 62 patients), which was not the
case with the lower dosage (3 of 54). ACTG 223 and CPCRA 027
have begun enrollment; no results are currently available.
4.
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10.
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13.
14.
15.
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17.
18.
19.
References
1. Rosenzweig DY. Pulmonary mycobacterial infections due to Mycobacterium intracellulare-avium complex. Clinical features and course in 100
consecutive cases. Chest 1979;75:115-9.
2. Horsburgh CR Jr, Mason UG III, Farhi DC, Iseman MD. Disseminated
infection with Mycobacterium avium-intracellulare. A report of 13 cases
and a review of the literature. Medicine (Baltimore) 1985;64:36-48.
3. Havlik JA Jr, Horsburgh CR Jr, Metchock B, Williams PP, Fann SA,
Thompson SE III. Disseminated Mycobacterium avium complex infec-
20.
21.
tion: clinical identification and epidemiologic trends. J Infect Dis
1992; 165:577-80.
Horsburgh CR Jr, Havlik JA, Ellis DA, et al. Survival of patients with
acquired immunodeficiency syndrome and disseminated Mycobacterium
avium complex infection with and without antimycobacterial chemotherapy. Am Rev Respir Dis 1991; 144:557-9.
Jacobson MA, Yajko D, Northfelt D, et al. Randomized, placebo-controlled trial ofrifampin, ethambutol, and ciprofloxacin for AIDS patients
with disseminated Mycobacterium avium complex infection. J Infect
Dis 1993; 168:112-9.
Chin DP, Reingold AL, Stone EN, et al. The impact of Mycobacterium
avium complex bacteremia and its treatment on survival of AIDS patients-a prospective study. J Infect Dis 1994; 170:578-84.
Horsburgh CR Jr, Metchock B, Gordon SM, Havlik JA Jr, McGowan JE
Jr, Thompson SE III. Predictors of survival in patients with AIDS and
disseminated Mycobacterium avium complex disease. J Infect Dis
1994; 170:573-7.
Benson CA. Treatment of disseminated disease due to the Mycobacterium
avium complex in patients with AIDS. Clin Infect Dis 1994; 18(suppl
3):S237 -42.
Rubin DS, Rahal n. Mycobacterium-avium complex. Infect Dis Clin North
Am 1994;8(2):413-26.
Masur H, the Public Health Service Task Force on Prophylaxis and Therapy for Mycobacterium avium complex. Recommendations on prophylaxis and therapy for disseminated Mycobacterium avium complex disease in patients infected with the human immunodeficiency virus. N
Engl J Med 1993;329:898-904.
Kemper CA, Havlir D, Haghighat D, et al. The individual microbiologic
effect of three antimycobacterial agents, clofazimine, ethambutol, and
rifampin, on Mycobacterium avium complex bacteremia in patients with
AIDS. J Infect Dis 1994; 170: 157-64.
Benson C. Disseminated Mycobacterium avium complex disease in patients with AIDS. AIDS Res Hum Retroviruses 1994; 10:913-6.
Heifets L. MIC as a quantitative measurement of the susceptibility of
Mycobacterium avium strains to seven antituberculosis drugs. Antimicrob Agents Chemother 1985;32:1131-6.
Heifets LB, Lindolm-Levy PJ, Flory MA. Bactericidal activity in vitro of
various rifamycins against Mycobacterium avium and Mycobacterium
tuberculosis. Am Rev Respir Dis 1990; 141:626-30.
Brogden RN, Fitton A. Rifabutin. A review of its antimicrobial activity,
pharmacokinetic properties and therapeutic efficacy. Drugs 1994;47:
983-1009.
Yajko DM, Nassos PS, Sanders CA, Hadley WK. Killing by antimycobacterial agents of AIDS-derived strains of Mycobacterium avium complex
inside cells of the mouse macrophage cell line 1774. Am Rev Respir
Dis 1989; 140:1198-203.
Kent RI, Bakhtiar M, Shanson DC. The in-vitro bactericidal activities of
combinations of antimicrobial agents against clinical isolates of Mycobacterium avium-intracellulare. J Antimicrob Chemother 1992; 30:
643-50.
Perronne C, Gikas A, Truffot-Pemot C, Grosset J, Pocidalo J-J, Vilde
J-L. Activities of clarithromycin, sulfisoxazole, and rifabutin against
Mycobacterium avium complex multiplication with human macrophages. Antimicrob Agents Chemother 1990; 34: 1508-11.
Gangadharam PRJ, Perumal VK, Jairam BT, et al. Activity of rifabutin
alone or in combination with clofazimine or ethambutol or both against
acute and chronic experimental Mycobacterium intracellulare infections. Am Rev Respir Dis 1987; 136:329-33.
Gangadharam PRJ, Perumal VK, Podapati NR, Kesavalu L, Iseman MD.
In vivo activity of amikacin alone or in combination with clofazimine
or rifabutin or both against acute experimental Mycobacterium avium
complex infections in beige mice. Antimicrob Agents Chemother
1988;32:1400-3.
Furney SK, Roberts AD, Orme 1M. Effect of rifabutin on disseminated
Mycobacterium avium infections in thymectomized, CD4 T-cell-deficient mice. Antimicrob Agents Chemother 1990;34:1629-32.
Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014
Another therapeutic option would be rifabutin in combination with azithromycin. The pharmacokinetic interactions between rifabutin and azithromycin are likely to be considerably
less than those seen with clarithromycin, since azithromycin
does not inhibit the cytochrome P-450 pathway [38]. Thus,
regimens containing azithromycin and rifabutin may incur a
smaller risk of toxicity.
Rifabutin may also be a useful alternative to macrolides.
As discussed above, combining rifabutin with ethambutol and
clofazimine resulted in a microbiological response in most patients. This finding suggests that such regimens would be of
value as initial therapy for patients intolerant of macrolides or,
alternatively, as maintenance therapy for patients who initially
respond to macrolides but who become intolerant of these
agents.
In addition to defining the clinical efficacy ofrifabutin, future
trials will need to examine several related therapeutic issues.
For example, it is unknown if rifabutin is less active in patients
who have disseminated MAC infection while receiving rifabutin prophylaxis. Although emergence of resistance was not
detected in the two large prophylaxis trials (Adria 023 and
027), these studies did not address the therapeutic response of
patients for whom rifabutin prophylaxis had failed [40]. Other
issues include the impact of rifabutin on the pharmacokinetics
of other drugs and the effects of rifabutin therapy for MAC
infection on resistance among other mycobacterial species.
These and related questions await resolution by pending
studies.
1996;22 (Suppl 1)
cm
1996; 22 (Suppl 1)
Rifabutin Therapy for MAC Infection
teremia: final results [abstract no LB-20]. In: Program and abstracts of
the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy (San Francisco). Washington, DC: American Society for Microbiology, 1995 (adden): 11.
Discussion
DR. MICHAEL TAPPER. Wasn't there a question about compliance in the high-dose arm of your trial of clarithromycin for
treatment of Mycobacterium
avium complex (MAC) infection?
DR. RICHARD E. CHAISSON. No, if you look at the results
of that study (ACTG [AIDS Clinical Trials Group] 157), the
mortality at 12 weeks among patients in the 500-mg arm was
3%; among those in the 1-g and 2-g arms, mortality was 14%15%. A time-to-death analysis showed that there was a significant difference between the low-dose and high-dose groups in
terms of mortality; there was no way to eliminate that difference. What this mortality difference means is not made clear
by the U.S. Food and Drug Administration label for clarithromycin for treatment of MAC infections; it actually says that
the reason for increased mortality is not known.
There are many speculations about this increased mortality.
One is that higher doses are lethal; another is that patients in the
low-dose arm were heartier and had better Kamofsky scores.
There are many possible reasons, but currently nobody knows,
or will ever know, why there was a higher mortality associated
with the higher doses in our
trial. It's an important question
has shown that higher doses
because Dr. Bertrand Dautzenberg
aren't more lethal, although they are more toxic and more microbiologically active. Whether there is a difference in mortality associated with the higher dose is an important question, which the
CPCRA MAC treatment
trial will address.
DR. TAPPER. How will azoles be used in this patient population? Should they be avoided?
DR. PAUL M. SULLAM. It's hard to say because the use of
azoles is so ubiquitous. This question is probably less of an
issue for patients receiving rifabutin but no macrolides. However, I suspect that patients who are also receiving macrolides
will probably have to get a lower dose. One objective of these
studies will be to fine-tune the dose.
DR. BERTRAND DAUTZENBERG. Have you submitted any
data on rifabutin preventing the development of resistance to
clarithromycin after 12 or
8 weeks
of treatment?
DR. FRED M. GORDIN. I think, Dr. Dautzenberg, you have
presented some other data on clarithromycin in various combinations that showed, if I'm correct, that ethambutol seemed to
prevent the development of resistance in MAC isolates.
DR. BEVERLEY WYNNE. On the basis of a preliminary look
at the data, we haven't observed any relapses in patients who
have cleared mycobacteria from the blood. However, we don't
have enough data at this time to answer the question. I want
to comment on the European MAC treatment trials, the United
States treatment trial, and the Canadian treatment trial, in which
60%- 70% of patients were receiving an azole (primarily flu-
Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014
22. Saito H, Sato K, Tomioka H. Comparative in vitro and in vivo activity of
rifabutin and rifampicin against Mycobacterium avium complex. Tubercle 1988; 69: 187-92.
23. Saito H, Sato K. Activity of rifabutin alone and in combination with
clofazimine, kanamycin and ethambutol against Mycobacterium intracellulare infections in mice. Tubercle 1989; 70:201-5.
24. Cynamon MH, Klemens SP. Activity of azithromycin against Mycobacterium avium infection in beige mice. Antimicrob Agents Chemother
1992;36:1611-3.
25. Klemens SP, Cynamon MH. In vivo activities of newer rifamycin analogs
against Mycobacterium avium infection. Antimicrob Agents Chemother
1991; 35:2026-30.
26. Lazard T, Perronne C, Grosset J, Vilde JL, Pocidalo JI. Clarithromycin,
minocycline, and rifabutin treatments before and after infection of
C57BLl6 mice with Mycobacterium avium. Antimicrob Agents Chemother 1993;37:1690-2.
27. Masur H, Tuazon C, Gill V, et al. Effect of combined clofazimine and
ansamycin therapy on Mycobacterium avium-Mycobacterium intracellulare bacteremia in patients with AIDS. J Infect Dis 1987; 155:
127-9.
28. Hoy J, Mijch A, Sandland M, Grayson L, Lucas R, Dwyer B. Quadrupledrug therapy for Mycobacterium avium-intracellulare bacteremia in
AIDS patients. J Infect Dis 1990; 161 :801-5.
29. Dautzenberg B, Truffot C, Mignon A, et al. Rifabutin in combination with
clofazimine, isoniazid and ethambutol in the treatment ofAIDS patients
with infections due to opportunist mycobacteria. Tubercle 1991;
72:168-75.
30. Sullam PM, Gordin FM, Wynne BA, The Rifabutin Treatment Group.
Efficacy of rifabutin in the treatment of disseminated infection due to
Mycobacterium avium complex. Clin Infect Dis 1994; 19:84-6.
31. Chiu J, Nussbaum J, Bozzette S, et al. Treatment of disseminated Mycobacterium avium complex infection in AIDS with amikacin, ethambutol,
rifampin, and ciprofloxacin. Ann Intern Med 1990; 113:358-61.
32. Kemper CA, Meng TC, Nussbaum J, et al. Treatment of Mycobacterium
avium complex bacteremia in AIDS with a four-drug oral regimen:
rifampin, ethambutol, clofazimine, and ciprofloxacin. Ann Intern Med
1992; 116:466-72.
33. Dautzenberg B, Saint Marc T, Meyohas MC, et al. Clarithromycin and
other antimicrobial agents in the treatment of disseminated Mycobacterium avium infections in patients with acquired immunodeficiency syndrome. Arch Intern Med 1993; 153:368-72.
34. Chaisson RE, Benson CA, Dube MP, et al. Clarithromycin therapy for
bacteremic Mycobacterium avium complex disease. A randomized, double-blind, dose-ranging study in patients with AIDS. Ann Intern Med
1994; 121:905-11.
35. Young LS, Wiviott L, Wu M, Kolonoski P, Bolan R, Inderlied CB.
Azithromycin for treatment of Mycobacterium avium-intracellulare
complex infection in patients with AIDS. Lancet 1991;338:1107-9.
36. Shafran SD, Deschenes J, Miller M, Phillips P, Toma E. Uveitis and
pseudojaundice during a regimen ofclarithromycin, rifabutin and ethambutol [letter]. N Engl J Med 1994;330:438-9.
37. The Datri 001 Study Group. Coadministration of clarithromycin alters the
concentration-time profile of rifabutin [abstract A2]. In: Program and
abstracts of the 34th Interscience Congress on Antimicrobial Agents
and Chemotherapy (Orlando, FL). Washington, DC: American Society
for Microbiology, 1994:3.
38. Periti P, Mazzei T, Mini E, Novelli A. Pharmacokinetic drug interactions
of macroIides. Clin Pharmacokinet 1992;23:106-31.
39. Havlir D, Torriani F, Dube M. Uveitis associated with rifabutin prophylaxis. Ann Intern Med 1994; 121:510-2.
40. Nightingale SD, Cameron DW, Gordin FM, et al. Two controlled trials
of rifabutin prophylaxis against Mycobacterium avium infection in
AIDS. N Engl J Med 1993;329:828-33.
41. Shafran SD, Singer J, Phillips P, Canadian MAC Study Group. The Canadian randomized open-label trial of combination therapy for MAC bac-
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DR. PHILLIPS. In the Canadian study, the duration of symptomatic uveitis was longer, usually on the order of several
weeks, before the association was recognized. But since this
association has become well known to investigators, treatment
with the drug is being stopped right away, and the duration of
symptoms is much shorter-on the order of 1 or 2 weeks.
DR. TAPPER. Could you speculate a bit more about a subject
you touched on: the role of drugs in terms of both induction
therapy and maintenance therapy? Some drugs, such as amikacin, come to mind as being rather useful as induction therapy
or perhaps as reinduction therapy after relapse, but perhaps not
for long-term maintenance therapy. What is the future oftherapy for MAC disease?
DR. SULLAM. I think tuberculosis, or perhaps more-conventional bacterial infections, is a model. Phase 1 is a regimen
that can produce either enduring suppression or sterilization;
phase 2 is one of more rapid response. One problem with the
early trials for MAC infection was that it would take many
weeks to get a response. With application of some of the newer
drugs such as macrolides and rifabutin, it's possible to achieve
the first phase of treatment. Time to sterilization is shortened
to 2 weeks, instead of 6 or 8 weeks. That shorter duration may
seem trivial, but for a patient whose life expectancy would
otherwise be 4 or 6 months, it is significant. It could also have
an impact on survival because the wasting syndrome associated
with MAC infection is arrested. I see phase 2 as one ofadjusting
regimens to effect prompt and lasting sterilization, with a third
phase consisting of simpler, safer regimens and compliance.
DR. TERRENCE F. BLASCHKE. Given the appropriate concern
about the variety of possible drug interactions and given that,
even without drug interactions, there may be substantial variability in the disposition of these drugs, particularly those that
are metabolized, I hope that some thought is being given to
taking advantage of the situation to monitor the patients who
develop toxicity and to determine serum concentrations of the
drugs so that we can establish whether the interactions themselves are in fact contributing to the incidence of the toxicities,
whether they be uveitis or any other toxicities.
DR. SULLAM. In the studies I've been involved with, such
as Pharmacia 065 and Pharmacia 250, the pharmacokinetics
and serum levels of the drugs are part of the analysis.
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conazole). The doses of azoles varied a lot in the trials, so it's
hard to say what the mean dose was.
DR. P. K. NARANG. Of the top 10 medications used, at
least in the prophylaxis trials, five of them are azoles (not
just fluconazole). Other azoles that can have similar inhibitory
properties are being used.
DR. SULLAM. An interesting sidelight of the rifabutin prophylaxis study was just how widely azoles are used. We had
discussed analyzing their use, but I think people are clearly
using these drugs for prophylaxis as well as treatment; however,
the evidence for their efficacy as prophylaxis is not definitive.
DR. TAPPER. It would be important to determine their efficacy, because there are significant differences in the dosages
used. For example, in Europe, the dosage of fluconazole is
often much lower than that commonly used in the United States.
The other issue is that there are significant differences in the
bioavailability of the azoles; fluconazole is more extensively
absorbed than are itraconazole or ketoconazole.
DR. GORDIN. Dr. Phillips, what has happened with the Canadian trial since the complication of uveitis was reported? Have
the dosages of rifabutin been changed, or are patients staying
in the trial while they are being treated for uveitis?
DR. PETER PHILLIPS. The dosage of rifabutin was changed.
Initially, it was 600 mg/d, and it was dropped to 300 mg/d
when the association was first noted. Since then, the safety
committee has conducted another review because of the development of acute cases of uveitis (now a total of three) at the
lower dose of 300 mg/d within that treatment combination.
However, the study continues despite these additional cases.
Our approach is to stop administering rifabutin when uveitis
develops, although some patients have been managed successfully by reintroducing the drug and continuing topical therapy
for uveitis (that's not the approach that's being taken by the
Canadian trials network). We are continuing to monitor these
patients closely, and we hope that we won't see an increase in
the number of cases of uveitis.
DR. DAUTZENBERG. How many patients were cured of uveitis after rifabutin was withdrawn?
DR. SULLAM. My understanding is that with recognition of
inflammation and withdrawal of the drug, all patients who
developed uveitis have recovered.
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