Advances in the treatment of disseminated Mycobacterium avium complex in adults with AIDS

Although the prospects for successful treatment of Mycobacterium avium complex (MAC) infection in AIDS recently seemed quite dismal, the introduction of 
the semisynthetic macrolides, clarithromycin and azithromycin, has altered this perspective. Several recent clinical studies have been key to our understanding of the successful management of these patients and are the basis of this review. Yet, some patients with disseminated MAC remain poorly responsive to therapy, intolerance often limits therapy, and recrudescent bacteremia often occurs. Though our understanding of this infection has been rapidly advanced in the past three years. much remains to be learned about its optimal therapeutic management.

tion, but intolerance to therapy was frequent, and most patients continued to have clinical and microbiological evidence of infection (1-6).Subsequently, a raft of newer data (including at least 10 studies of combination therapy and eight of single-agent therapy).demonstrating the short term antibacterial effect of multidrug and single-drug regimens, have enhanced our ability to manage this infection.These data provide a rationale for the recent United States Public Health Service guidelines which advocate the use of a macrolide, either clarithromycin or azithromycin, in combination with at least one other antimycobacterial agent, in the treatment of MAC infection in adults with AIDS (7).
Early reports suggested that disseminated infection due to MAC in patients with AIDS could be ameliorated using multiple antimycobacterial agents in combina-Highlights of several recent studies and a brief over-

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nt of Mycobacterium avium bacteremia view of ongoing clinical trials are the subject of this discussion: two recent reviews provide additional information (8,9).

EARLY CLINICAL TRIALS
Recognizing elimination of mycobacteremia as the single tangible measure of antimycobacterial efficacy, Masur and colleagues (6) examined the effect of a combination of clofazimine (100 mg once daily) and rifabutin (150 lo 300 mg once daily), in addition to a variety of other antimycobacle1;al agents, on MAC bacteremia in 13 patients for various durations (16 to 303 days).Although t.he authors were disappointed by their results (seven of 13 patients had at least two negative blood cultures.but two later developed recrudescent bacteremia), these data were an early signal that.aggressive therapy with multiple agents could effect.a microbiological response in some patients.
Hoy et al (4) identified 76 AIDS patients with MAC bacteremia.Twenty-two of 25 patients who tolerated a combination of isoniazid, clofazimine, ethambutol and rifabutin for more than 30 days had at least two consecutive negative blood cultures.Five subsequently relapsed.One of four patienls who responded lo the therapy, but subsequently died, had evidence of MAC at autopsy.However, no data were available on the other 51 patienls.Similar results were demonstrated in another smaller study (1).
The results of these early studies provided a harbinger of a now well recognized fact: eradication of MAC in the blood stream is not equivalent to microbiological cure (tissue infect.ionmay be present in the absence of detectable bacteremia) and, despite initial sterilization of blood, recrudescence of mycobacterelnia is frequent.For this reason, the relationship of mycobacterelnia to tissue levels of infection in bone marrow is currently being examined in a longitudinal treatment study (Division of AIDS Treatment Research Initiative [DATRJJ Protocol 007).

MULTIDRUG REGIMENS (WITHOUT A MACROLIDE)
Hawkins et al (3) and Wong et al (5) were the first investigators to recognize that quantitatively-determined mycobacleremia may be a useful measure of antibacterial activily in humans, and all studies discussed below employed lhis methodology.
Chiu and colleagues (10), through the California Collaborative Treatment Group (CCTG) , were the firsl to examine the effect of multiple agents.in combination, on the numbers of circulating mycobacteria in a group of patients with AIDS .Seventeen patients with MAC bacterelnia received parenlerally administered amikacin (7 .5 mg/kg/day) for four weeks in combination with orally administered ciprofloxacin (750 mg bid).rifampin (600 mg once daily).and ethambutol (1000 mg once daily) for 12 weeks.After four weeks , mean pretreatment colony counts fell from 537 colony forn1ing units (cfu)/rnL of blood to 14 cfu/mL in 15 patients (-1.5 log10 cfu/mL).Colony counts remained suppressed (mean, 15 cfu/rnL) in 10 patients who completed the 12-week study, and three of these patienls had clearance of bacteremia.Fevers, sweals and diarrhea improved in several patients who could tolerate the regimen.but three patienls (18%) were wilhdrawn from study for gastrointestinal side effecls.Colony counls remained suppressed (mean, 0.1 cfu/mL) in eight patients who conlinued the three oral agents for an average of 22 weeks of therapy.
This study was the first to demonslrale that reductions in quantitatively delermined mycobacleremia were associated with improvemenl in clinical symptoms in patients who could tolerate therapy.However, inlolerance to therapy was frequent and amikacin was difficult to administer.
Clofazilnine ( 100 t.o 200 mg once daily) was therefore substituted for amikacin in a second phase of this study, resulting in a regimen of four drugs, all given per os (11).In order to evaluale the initial anlibacterial effect of the oral agents in combination, the use of amikacin was restricted to the second four weeks of study at the discretion of the investigator.A tot.al of 41 patients was enrolled.31 of whom were evaluable with regard to the antibacterial effect of lhe regimen, but.only 19 patients completed the 12-week study.Mean logarithlnically delermined colony counts fell from 2.1 log10 cfu/mL to 0.7 log10 cfu/mL after four weeks of therapy in 29 individuals, and lo 0.1 log10 cfu/mL after 12 weeks of therapy in 19.Thirteen patients (42%) had at least one blood culture negative for MAC.Again, dramatic reductions in colony counts were seen within the first four weeks of therapy, often associaled with improvement in clinical symploms.The mean individual change in colony counts (-1.4 log10 cfu/mL) after four weeks of treatment was comparable with lhal of the previous regimen using amikacin.Alt.hough eight patients received amikacin after lhe first four weeks of study, there did not appear to be any additional significanl impact on colony counts; unfortunately, two of these patients died before week 8, yielding a very small subset for analysis.
Prelilninary dala from lhe AIDS Clinical Trials Group (ACTG Protocol 135) also suggesl that.the addition of amikacin to lhe four-drug combination used by lhe CCTG does not.resull in any grealer antibacterial activity than that of lhe four-drug regimen alone (9).Alt.hough its clinical efficacy has nol been clearly demonstrated , amikacin remains one of lhe most active agenls in vitro and in the animal model, and is likely to remain a useful agent, particularly in those patienls who can nol tolerale oral therapy, are severely ill or are hospilalized.
Jacobson and colleagues (12) al lhe University of California, San Francisco is one of two groups lo have attempled a placebo-controlled treatment trial of MAC in AIDS.Twenty-four patients were randomized t.o receive ciprofloxacin (750 mg once daily).rifampin (600 mg

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once daily), and etharnbutol (25 mg/kg daily) or matching placebos; in addition, patients received ibuprofen as needed.While four of nine drug recipients had a microbiological response (defined as a 1.0 log or greater decrease in baseline colony counts), none of 10 placebo recipients did.Only one of 10 patients failed active drug treatment (defined as a 1.0 or greater increase in baseline colony counts).while seven of 10 placebo recipients had an increase in the level of mycobacteremia.While not a statistically significant difference, only one of 12 drug recipients versus four of 12 placebo recipients became moribund and were withdrawn from study.Originally intended as a crossover treatment trial, so few patients in the placebo arm remained after eight weeks that the investigators abandoned the original study design in favour of continued treatment.These were the first controlled data to support the long-held belief that, in the absence of therapy, colony counts increase in the majority of patients.
Rifabutin recently made its entrance as a useful agent in the prophylaxis of MAC.Although it has been used in a number of moderately successful multidrug treatment regimens, its contribution to these regimens has not been clear.In a recent treatment trial, 40 patients were randomized to clofazimine and etharnbutol with or witl10ut rtfabutin (13).After four weeks of therapy, seven of 11 patients who received the threedrug combination had a microbial response (six had clearance of mycobacteremia and one had more than a 2 .0log10 reduction in colony counts).In contrast, none of the 13 patients who received the two-drug combination responded.After 12 weeks of therapy, six of nine patients remaining on the three-drug arm had a microbial response versus only one of seven of those who received clofazirnine and etharnbutol.This study has since been terminated in favour of one using clarithromycin-containing regimens.
Compounding the interpretation of the results of these studies was the demonstration by Horsburgh et al ( 14) that absorption of many antimycobacterial agents is, at best.marginal in the majority of patients with AIDS.In a group of27 patients with MAC bacteremia treated with clofazirnine, ciprofloxacin, etharnbutol and rifarnpin, 20 of whom tolerated at least three agents for eight weeks, only three patients had serum concentrations of a single-agent that fell within the expected range.Peak serum levels for 77 of the 80 assays ranged from borderline 'therapeutic' in two assays to undetectable in 29 (36%).Nevertheless, six patients had clearance of mycobacteremia.These observations have important implications for clinical practice and the conduct of treatment trials.

SINGLE-AGENT STUDIES
In an attempt to define the individual antibacterial activity of several agents used in the previous modestly successful ccrc regimens, 60 patients were randomized 16B to receive either clofazimine (200 mg once daily).ethambutol (800 mg daily) or rifampin (600 mg daily) for four weeks ( 15).This short term efficacy trial yielded unexpected results; while colony counts were not significantly changed in response to the administration of either clofazimine or rifarnpin.they fell a median of 0.6 log10 cfu/mL in response to four weeks of ethambutol.These data proved that, in contrast to much in vitro data but confirming animal data, etharnbutol has modest antibacterial activity in vivo, and supports its inclusion in combination regimens (7).
The lack of a significant decrement in mycobacteremia in response to either rtfarnpin or clofazimine does not necessarily indicate a total lack of antibacterial effect.Based on limited data that colony counts increase in the absence of therapy (12,16).each of these agents may have prevented an increase in colony counts and could therefore be considered bacte1iostatic in vivo.
While the individual activity of these three agents does not fully account for the observed bacteriological activity of the previous CCI'G regimens, it is unlikely that this difference can be accounted for solely by the addition of ciprofloxacin in the earlier regimens.In a similar study.sparOoxacin (200 lo 300 mg daily), a fluoroquinolone with slightly better in vitro activity than ciprofloxacin, had little effect on mycobacterial colony counts in blood when administered as a single-agent for four weeks (17).However, when etharnbutol was added for another four to eight weeks, colony counts fell a mean of 0.95 log10 cfu/mL in 18 of 22 patients.
Nightingale and colleagues (18) administered lipidassociated gentamicin (TLC G-65) in three doses ranging from 1. 7 mg/kg to 5.1 mg/kg once daily for approximately six weeks to 21 AJDS patients with MAC bacteremia (17).Mean pretreatment colony counts were reduced by over 90% at day 32; in 14 evaluable patients, individual colony counts fell a median of 0.45 log10 cfu/mL.No apparent difference in bacteriological efficacy between the three doses was detected, but the study was prematurely discontinued when one patient (who received the higher dose) developed reversible nonoliguric renal failure.No other adverse effects were identified.
No other single-agent or combination of agents to date has demonstrated the remarkable antimycobacterial effect of the semisynthetic macrolides, clarithromycin and azithromycin.In a placebo controlled crossover treatment trial, one group of eight patients received clarithromycin alone for six weeks , and then a combination of clofazimine, etharnbutol, isoniazid and rifarnpin plus placebo for six weeks (16).A second group of seven patients received placebo for six weeks, and then a combination of clarithromycin plus the four other agents.Clearance of bacteremia was documented in six of eight patients after administration of clarilhromycin alone.After discontinuation of clarithromycin, mycobacleremia increased in three patients.of seven who received placebo alone had increasing levels of mycobacteremia (and the other two died).These were the first controlled data to support.the long-held belief that, in the absence of therapy, colony counts increase in the majority of patients.

ONLY• TABLE 1 Commonly used antimycobacterial agents in the treatment of disseminated infection due to Mycobacterium a vium complex in adults with AIDS
In a randomized , dose-ranging study of clarithromycin in the treatment of MAC bacteremia in AJDS (ACTG 157).154 patients received either 500 mg, 1.0 g or 2 .0g bid for 12 weeks (19,20).Preliminary results showed eradication of mycobacteremia in more than 50% of the patients by four lo six weeks; median times lo sterilization of b lood cultures were 27, 43 and 55 days, respectively.Pretreatment colony counts, ranging from 2.6 lo 2.8 log10 cfu / mL, fell a mean of 1.5, 2 .4 and 2.3 log10 cfu/mL, respectively.In addition, clinical symptoms and quality of life were improved in patients who received either 500 or 1000 mg b id.However, 15%, 16% and 40% of patients prematurely discontinued study, respectively, most due to gastrointestinal side effects.
Suppression of bacteremia proved to be short-lived in many patients; recrudescence associated with high level resistance (minimum inhibitory concentration [M IC] 128 µg / mL or greater) occurred in 61 patients a mean of 16 weeks after entry into the study.The MJCs of 180 isolates obtained from patients who relapsed were examined: only 29 (16%) were 8 µg/mL or less and 151 (84%) were 128 µg / mL or greater.Thus the post.treatment.microbial isolates demonstrated a clearly biphasic popu lation consistent with a single mutation leading to h igh level resistance.
In a second similar st.udy, 299 patients were randomized to receive clarithromycin either 500 mg or 1.0 g bid for four weeks (21) .Preliminary data showed that mycobacteremia fell by 1.0 log10 or more in 72% of those who received the lower dose and 82% of 1.hose who received the higher dose; clinical improvement was noted in 75% and 82% , respectively.
Apparently comparable antibacterial activity has been demonstrated in response to azithromycin in two studies.The first, conducted by Young el al (22).included 21 patients who received 500 mg daily for 10, 20 and 30 days.Colony counts were reduced from 118 cfu/mL to 43 cfu/mL in three patients after only 10 days; after 20 to 30 days, colony counts fell from 2028 cfu/mL to 136 cfu/mL.Fifteen of 21 patients had resolution of fever and 12 of 18 had resolution of sweats, but. the mean weight decreased slightly.
In the second st.udy, azithromycin, either 600 mg or 1200 mg daily, was administered for six weeks lo 89 patients with AJDS and MAC bacteremia, 65 of whom were evaluable with regard lo antimicrobial efficacy (23).Similar reductions in MAC colony counts were demonstrated for both treatment arms; after six weeks of treatment, colony counts fell 2.0 log10 in those who received 600 mg daily and 1. 55 log Io in those who r eceived 1200 mg daily.Sterilization of b lood cultures was achieved in 56% and 42% , respectively.While 10% of those at the lower dose experienced nausea and diarrhea (none of which was dose-limiting), approximately 40% of patients at the higher dose experienced gastrointestinal toxicity ( 11 % of which was dose-limiting).MICs remained stable and low during the six-week study, but.resistance.including cross-resistance to clarithromycin, was demonstrated in the post.-st.udyperiod.

MULTIDRUG REGIMENS (WITH A MACROLIDE)
Several stud ies are available by which to gauge the efficacy of clarithromycin in combination with other antimycobacterial agents.De Lalla et al (24) used amikacin (7.5 mg/kg bid) for the first three weeks in combination with clarithromycin (LO g bid) and ciprofloxacin (500 mg lid) for 10 to 44 weeks in 12 patients with AIDS and MAC bacteremia.Sterilization of blood cultures was achieved in all 12 patients within two to six weeks of therapy.Three of four patients who died 12 to 44 weeks after entry into study had no histological or microbiological evidence of MAC at autopsy.Similar results were obtained using a combination of clarithromycin and clofazimine in 18 patients (25).An open multicentre llial of clarithromycin in combination with one or more additional antimycobacterial agents showed that mycobacteremia was eliminated in 11 of 16 evaluable patients who received 500 to 1000 mg daily, and 45 of 46 of those who received 1500 to 2000 mg daily (26).Acquired resistance to therapy was observed within two to seven months of study entry.

18B
Recognition that the monocyte/macroph age is the dominant site at which MAC reside has led to a novel attempt at immunomodulatory therapy using granu locyte-macrophage colony stimulating factor (GM -CSF).Preliminary results from a controlled, randomized trial of azithromycin (600 mg daily) with or without GM -CSF indicate that this cytokine enhanced superoxide production and intracell u lar killing of mycobacteria in one patient with disseminated MAC relative to an untreated control (27).

SUMMARY TREATMENT GUIDELINES
Based on these data, the United States Public Health Service has recommended that adults with human immunodeficiency virus (HIV) infecti.on and disseminated MAC receive one of the macrolide agents in combination with at least one other antimycobacterial (7) (Table 1).Which agent or agents will provide the optimal bacteriological activity in combination with the macrolides has not been determined, but most experts start with a combination of clarithromycin and eihambutol.While the relative efficacy of the two macrolides has not yet been determined.clarithromycin and azithromycin appear to have.al least in preliminary trials, comparable efficacy.While many clinicians add a t.hird agent (usually clofazimine).the value of this practice vis-a-vis t.olerabilit.yand long term effectiveness remains uncertain.but is being addressed by several groups (Table 2).Monitoring of t.he serum concentrations of administered drugs may prove useful, but further data are needed.
Initial treatment.is oft.encomplicated by gastrointestinal symptoms, which may be the result of drug administration.MAC involvement of the gastrointestinal tract, or both.While a chosen therapy may be initially poorly tolerated.once the infection is under some control.reintroduction of that agent may be successfully alt.empted.
Susceptibility studies on the baseline isolate are not believed to be of benefit in the initial selection of therapy.All pretreatment isolates have been susceptible to the macrolides and in vitro studies of susceptibility to clofazimine, et.hambulol or rifampin are of questionable

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TABLE 2 Ongoing and future clinical treatment trials of Mycobacterium avium complex in adults with AIDS Lead or sponsoring organization Total number of patients (number enrolled) * Treatment arms Ongoing studies
• Approximate number of patients enrolled as of March 7 993.t Prematurely terminated as of January 1994.GM-CSF Granulocyte-macrophage-colony stimulating factor