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Azithromycin-Containing Regimensfor Treatment of Mycobacterium aviumComplex Lung Disease David E. Griffith,1,3 Barbara A. Brown,2 William M. Girard,1 Bryan E. Griffith,2 Leslie A. Couch,1
and Richard J. Wallace, Jr.1,2
Departments of 1Medicine and 2Microbiology and the 3Center for Pulmonary and Infectious Disease Control, the University of Texas HealthCenter, Tyler, Texas Ninety-two patients were assessable in 3 consecutive, open, noncomparative, prospective, controlled, single-
center trials of the use of multidrug regimens that contain azithromycin for treating pulmonary Mycobacterium
avium complex (MAC) disease. Azithromycin was provided at a dose of 300–600 mg per day with oral
companion drugs administered daily (regimen A, 29 patients); 600 mg 3 times weekly (t.i.w.), with oral
companion drugs administered daily (regimen B, 20 patients); and 600 mg t.i.w., with oral companion drugs
administered t.i.w. (regimen C, 43 patients). All regimens included rifabutin (or rifampin) and ethambutol as
companion drugs as well as initial streptomycin. Treatment success was defined as 12 months of negative
cultures while on therapy. Treatment failure was defined as sputum culture positivity after at least 6 months
of therapy. Of the patients in each regimen who reached study end points, 17 of 29 (59%) were in regimen
A, 11 of 20 (55%) were in regimen B, and 28 of 43 (65%) were in regimen C met the treatment success
criterion. There were no statistically significant differences in outcome between the 3 regimens. These studies
demonstrate the effectiveness of daily and t.i.w. regimens containing azithromycin for treatment of MAC lung
disease.
Macrolide and azalide antibiotics, including clarithro- complex (MAC) disease [1–3]. We previously reported mycin and azithromycin, are currently the most impor- initial results after 6 months of therapy from 3 consec- tant component of multidrug treatment regimens for utive, open, concomparative, prospective, controlled, pulmonary and disseminated Mycobacterium avium single-center trials of azithromycin-containing regimens(ACRs) as therapy for HIV-negative patients with MAClung disease [4, 5]. The first report evaluated initial re-sponses to a daily administration of azithromycin mono- Received 24 April 2000; revised 10 October 2000; electronically published 4 therapy and a multidrug ACR; the second report eval- Presented in part: American Thoracic Society Annual Meeting, Chicago, May uated initial responses to administration of 2 intermittent multidrug regimens containing azithromycin for MAC Appropriate informed consent was obtained and clinical research was conducted in accordance with guidelines for human experimentation as specified by the lung disease. These studies suggested that during the first institutional review board of the University of Texas Health Center, Tyler, and the 6 months of therapy, azithromycin has significant activ- US Department of Health and Human Services.
ity, comparable to clarithromycin, when used either on Financial support: Pfizer Pharmaceuticals (Groton, CT) and Pharmacia & Upjohn a daily or intermittent (3 times weekly, or t.i.w.) basis in Reprints or correspondence: Dr. David E. Griffith, University of Texas, Health multidrug regimens for MAC lung disease.
Center at Tyler, 11937 US Hwy 271, Tyler, TX 75708-3154 ([email protected]).
We report on the long-term results of the 3 ACRs Clinical Infectious Diseases
2001; 32:1547–53
in HIV-negative patients with pulmonary MAC disease.
2001 by the Infectious Diseases Society of America. All rights reserved.
The goal of these ongoing clinical trials is to identify • CID 2001:32 (1 June) • 1547
Protocols for treatment of Mycobacterium avium complex lung disease using regimens that contain
azithromycin.
b.i.w., 2 times weekly; MWF, Monday, Wednesday, and Friday; t.i.w., 3 times weekly.
a Regimen A consisted of oral administration of all drugs daily. Regimen B consisted of azithromycin on MWF and oral administration of other drugs daily. Regimen C consisted of oral administration of drugs on MWF.
b Streptomycin dosage was individualized on the basis of age, weight, and renal function.
the most effective, least toxic combination of drugs that can jects Investigation Committee and by the US Food and Drug be used in multidrug therapeutic regimens for MAC pulmonary Administration under Investigational New Drug applications for azithromycin and rifabutin. All patients who met inclusioncriteria, signed an informed consent form and received studymedications are included in the intent-to-treat category.
PATIENTS AND METHODS
Therapy.
The 3 azithromycin treatment protocols are out- Patients and disease.
lined in table 1. All medications were self-administered. Patient MAC lung disease or referred to at the University of Texas compliance was evaluated by direct patient questioning and Health Center at Tyler (UTHCT) were considered for therapy.
monitoring of medication prescription refills. All patients in- Diagnostic criteria for lung disease included у2 sputum sam- itially received a 300-mg or 600-mg tablet of azithromycin (a ples that contained moderate-to-large numbers of organisms special dosage formulation of azithromycin provided by Pfizer on culture and an abnormal chest radiograph consistent with Pharmaceuticals) taken either daily or t.i.w. on Monday, mycobacterial lung disease, in agreement with the most recent Wednesday, and Friday, 2 h before or after a meal. In addition, criteria of the American Thoracic Society [1]. Features of the patients received companion drugs either daily or t.i.w. Orally pretreatment chest radiograph, history of antituberculosis drug administered companion drugs were taken on an empty stom- therapy, records of acid-fast bacilli smears, and culture results ach, and to encourage compliance, patients were asked to take and patient demographic information were recorded. Patients were considered to have been on previous therapy if they re- Regimen A consisted of azithromycin 300–600 mg/day (dosage ceived у6 months’ treatment with antituberculosis drugs with based on age and weight); ethambutol, 25 mg/kg/day for 2 or without a macrolide. Patients were considered to be current months, then 15 mg/kg/day; rifabutin, 300 mg/day (provided by smokers if they continued to smoke while on MAC therapy Pharmacia & Upjohn) or rifampin, 600 mg/day; and strepto- and former smokers if they had stopped smoking before en- mycin, usually included for the first 2 months of therapy given 2–3 times weekly with dosage adjusted for age, weight, and renal Study criteria.
Inclusion criteria included the presence of function. Regimen B consisted of azithromycin, 600 mg t.i.w., culture-positive sputum for MAC before any drug treatment with daily administration of oral companion medications as out- or at the time of entrance into the study and patient reliability lined in regimen A. Regimen C consisted of t.i.w. administration and availability for long-term follow-up. Patients could be ei- t.i.w. of all oral drugs in the regimen, including ethambutol, 25 ther hospital inpatients or outpatients. Exclusion criteria in- mg/kg, and rifabutin, 300–600 mg (dosage based on patient body cluded pregnancy, inadequate birth control, macrolide allergy, weight), or rifampin, 600 mg. The initial choice of rifabutin or life-threatening illness with no previous therapy for MAC lung rifampin was dictated by the availability of rifabutin. Strepto- disease, resistance to macrolides in a pretreatment MAC isolate, mycin was also usually included for the first 2 months of therapy, and identified risk factors or known seropositivity for HIV.
given 2–3 times per week with dosage adjusted for age, weight, Patients were considered for inclusion into the study, regardless and renal function. All patients considered in this analysis re- of previous therapy for MAC, as long as the pretreatment MAC ceived 3 orally administered drugs (azithromycin, ethambutol, isolate was macrolide susceptible. Informed consent was ob- and rifabutin or rifampin) throughout the study.
tained under a protocol approved by the UTHCT Human Sub- Acid-fast bacilli smears and cultures.
1548 • CID 2001:32 (1 June) • Griffith et al.
sputum specimens (1 specimen per day for 3 days) were collected value if they were already abnormal. Routine audiograms were at entrance into the study, and at least 1 specimen was taken also performed on entry for the first 31 patients and for any every 4 weeks during therapy. Sputum samples were decontam- patient who had a subjective decrease in auditory acuity. Rifa- inated with N-acetyl-L-cysteine and sodium hydroxide (NALC/ butin was discontinued if the patient’s WBC count fell below NaOH) [6]. Semiquantitative acid-fast bacilli smears (fluoro- 2 ϫ 10 cells/mm3, or the absolute granulocyte count fell below chrome method) were performed at a magnification of ϫ200, 1 ϫ 10 cells/mm3, or the platelet count fell below as described elsewhere [7]. Samples were plated on Middlebrook 7H10 agar and into BACTEC 12B broth (Becton-Dickenson).
Visual acuity and red-green color discrimination were tested Cultures that used solid media were quantitated from no growth on entry, at monthly intervals, and whenever the patient com- to 4ϩ by use of published standards and as described elsewhere plained of a sudden change in vision (blurred vision). In the [7]. For patients whose initial sputum specimens were contam- latter circumstance, the ethambutol was discontinued and con- inated (especially with Pseudomonas aeruginosa), subsequent sultation with the patient’s ophthalmologist was sought. Pa- samples were processed initially with NALC/NaOH, then proc- tients unable to tolerate rifabutin (patients who experienced essed a second time with oxalic acid [6]. In addition, samples fever, chills, nausea, vomiting, or leukopenia) were switched to were also inoculated onto a 7H10 agar plate containing 10 mg/ rifampin, 600 mg. Patients unable to tolerate either rifamycin mL of tobramycin. Organisms were identified as MAC with a or ethambutol were dropped from the study. If patients were commercial nucleic acid probe (AccuProbe; GenProbe).
unable to tolerate 600 mg of azithromycin, we decreased the Sputum conversion was defined as 3 consecutive cultures dose to 300 mg. Patients unable to tolerate 300 mg of azith- negative for MAC (both solid media and BACTEC) with the romycin were dropped from the study.
time of conversion the date of the first of 3 negative sputum Statistical analysis.
cultures. Treatment success was defined as 12 consecutive עSD. Comparison of characteristics between patients with and months of negative cultures while the patient was on therapy.
without sputum conversion and between treatment groups was Failure to respond to treatment was defined as persistently done by an unpaired t test with a 2-tailed P value. Comparison positive sputum cultures (failure to convert sputum cultures of culture results in patients who did or did not respond before to negative) after at least 6 months of therapy. Patients were and at the end of therapy and comparison with previous clar- dropped from the study and classified as noncompliant if they ithromycin treatment groups were done by x2 analysis and did not keep follow-up appointments and did not obtain med- Fisher’s exact test with Yate’s correction for small sample sizes.
ication refills before completing 6 months of therapy.
Significance was determined at P р Macrolide susceptibility testing.
as the class drug for testing macrolide and azalide susceptibility.
A pretreatment isolate of MAC and selected isolates on treat-ment were subcultured once on 7H10 agar. Clarithromycin A total of 103 HIV-negative patients were enrolled in the 3 MICs were then performed with broth microdilution with 2- ACRs (table 2) in the intent-to-treat category: 32 in regimen fold drug dilutions in Mueller-Hinton broth supplemented with A, 22 in regimen B, and 49 in regimen C. There were no 5% oleic acid, albumin, and dextrose; pH 7.4; and 2-week differences demographically (mean age at enrollment, sex, incubation, as described elsewhere [8, 9]. Isolates were consid- smoking history, or type of MAC lung disease) between the ered to be macrolide-azalide susceptible if they had clarithro- intent-to-treat patients in these 3 treatment regimens (table 2) mycin MICs р8 mg/mL and resistant if they had MICs у32 or compared with patient populations from our previous treat- mg/mL. Each isolate was frozen at Ϫ70ЊC for future use.
ment trials [7, 10]. Eleven patients (11%) were excluded be- Drug tolerance and safety tests.
cause of noncompliance. Ninety-two patients (89%) reached about problems and symptoms (especially gastrointestinal, au- study end points, either negative cultures for 12 months while ditory, and vestibular symptoms) at entry and on each clinic they were receiving therapy or persistently positive cultures after visit. In addition, a study coordinator was available 5 days each at least 6 months of therapy. Of the patients in each regimen week by telephone. Laboratory safety tests consisted of baseline who reached study end points, 59% in regimen A, 55% in liver enzymes (including a glutamyl transpeptidase and alkaline regimen B, and 65% in regimen C met the treatment success phosphatase), blood urea nitrogen, serum creatinine, and com- plete blood count. The liver enzyme test and complete blood All patients who met the treatment success criterion had count were done at monthly intervals for 6 months. An increase symptomatic improvement in cough and fatigue, and most had in liver enzymes was considered to be present if the enzymes radiographic improvement, although for cost reasons, serial CT rose during therapy to twice the upper limits of normal (if base- scans that would have provided more detailed results were not line values were normal), or if they rose to twice the baseline performed. There were no statistically significant differences in Azithromycin for MAC Lung Disease • CID 2001:32 (1 June) • 1549
Characteristics of 103 patients enrolled in azithromycin trials.
a Percentages calculated based on total assessable.
b Dropped out of the study before 6 months of follow-up.
outcome between the 3 ACRs (table 3). However, treatment (16%) of the 56 patients who successfully completed therapy outcomes with regimens A and B were significantly different .02 . Of the patients who had received previous therapy, from a study published elsewhere [10] that used a daily clar- only 9 (38%) of 24 were successfully treated in this trial, com- ithromycin regimen with identical companion drugs; regimen pared with success with 46 (68%) of 68 of those patients with C was not significantly different from any comparison regimen no previous therapy (P p .01). There was no significant dif- ference in the dropout rates between patients who had failed Twenty-seven patients (29%) from the 3 regimens received previous therapy and patients who were not previously treated.
rifampin instead of rifabutin as part of the initial treatment In general, azithromycin was tolerated well, both on a daily regimen. As observed in previous studies from this institution, and intermittent basis. However, 6 patients in regimen A (21%) there were no statistically significant differences in outcome required a decrease in azithromycin dose, 5 because of de- between patients who received rifabutin and those who received creased auditory acuity, and 1 because of gastrointestinal symp- rifampin in any of the 3 regimens [4, 5, 7, 10].
toms. Two patients (10%) in regimen B and 2 patients (5%) There were also no significant demographic differences in in regimen C (1 patient from each regimen because of decreased the parameters in table 2 between the patients who met the auditory acuity and 1 patient from each regimen because of treatment success criterion and the patients who did not. Of gastrointestinal symptoms) required azithromycin dosage ad- the 36 patients from all 3 regimens who failed to respond to justment (P ! .05 compared with regimen A). Four patients therapy, 11 (30%) had a history of alcohol abuse during therapyand 26 (72%) were current or former smokers, versus 9 (16%) from regimen A, all of whom received 4 months of initial azithromycin monotherapy, developed macrolide-resistant tients who successfully responded to and completed therapy.
MAC isolates. No MAC isolate from patients receiving inter- As in previous reports, there were no differences in type or mittent azithromycin in combination with rifabutin and etham- extent of lung disease between patients who had successful butol, without an initial course of monotherapy, developed therapy and patients who failed to respond to therapy [4, 5, 7, As was the case in previous studies, rifabutin was the drug There was, however, a significant difference in response rates most frequently associated with adverse events (gastrointestinal when comparing patients who did not respond to therapy on symptoms, arthralgia, fever, chills, and leukopenia). For patients a previous 6-month or longer course with those who did not initially placed on rifabutin, 37% in regimen A, 37% in regimen respond. Of the 36 patients who failed to respond to therapy B, and 32% in regimen C required rifabutin dosage adjustment in the 3 trials, 15 (42%) had previous MAC therapy, versus 9 or discontinuation. Two patients in regimen A who received daily 1550 • CID 2001:32 (1 June) • Griffith et al.
Treatment outcome for azithromycin regimens compared with a trial of daily clarith-
romycin with the same companion drugs from the same study site.
a Derived from [2].
b P ! .05 compared with daily clarithromycin regimens.
c No statistical difference compared with the other 3 regimens.
d All these patients received 4 mo of initial azithromycin monotherapy.
e Five of these patients received at least 3 mo of initial clarithromycin monotherapy.
ethambutol experienced deterioration of visual acuity sufficiently disease. It is therefore surprising that at least some ACRs appear severe to require discontinuation of ethambutol.
to be less effective than CCRs that used similar companion There are few studies directly comparing the efficacy of ACRs DISCUSSION
and CCRs for the treatment of either pulmonary or dissemi- Three ACRs for MAC lung disease were evaluated in open, nated MAC lung disease. Ward et al. [15] compared azithro- prospective, noncomparative trials. The treatment regimen in mycin, 600 mg/day plus ethambutol versus clarithromycin, which all medications were given on an intermittent basis 1000 mg/day, plus ethambutol in the treatment of MAC bac- yielded results comparable to those obtained with a daily clar- teremia in AIDS patients. Patients were evaluated every 4 weeks ithromycin-containing regimen (CCR). Two other ACRs that for 16 weeks. Fifty-nine patients were enrolled, but only 37 included a daily treatment component did not achieve the same patients (21 in the clarithromycin study arm and 16 in the level of success. One of these regimens, including daily azith- azithromycin study arm) were available for determination of romycin, was also associated with significantly more azithro- quantitatively defined bacteremia and clinical outcomes. The mycin-related toxicity. Additionally, as we have consistently ob- proportion of patients with clearance of bacteremia at the final served, previous unsuccessful therapy for MAC lung disease study visit (at 16 weeks) was 37.5% in the study’s azithromycin was a significant predictor for failure to respond to treatment, arm and 85.7% in the study’s clarithromycin arm (P p even in the presence of macrolide-susceptible MAC isolates [4, Additionally, the estimated median time to clearance of bac- teremia was significantly different for the 2 treatment groups: Theoretically, azithromycin should be a good drug for treat- 4.4 weeks for the clarithromycin arm versus 116 weeks for the ment of MAC lung disease. Levels of azithromycin that exceed azithromycin arm. There was no difference between the 2 treat- the MIC for MAC are not obtainable in the serum; however, ment arms in clinical (symptomatic) response. Both azithro- they can be achieved intracellularly and specifically within the mycin and clarithromycin were tolerated well, with few side macrophage [11–14]. Intracellular levels of azithromycin are effects, and no patient required discontinuation of either drug.
also maintained up to 2–3 weeks after dosing; therefore, in- In this relatively brief study period, only 1 patient in the study’s tracellular pathogens, such as MAC, would be exposed to high clarithromycin arm developed macrolide-resistant MAC. Ward levels of azithromycin for substantial periods of time. The sus- et al. [15] do not offer explanations for the differences in mi- tained concentration of azithromycin in phagocytic cells un- crobiologic response between ACRs and CCRs.
doubtedly contributes to its efficacy when it is administered on In a larger, more recent multinational study, Dunne et al.
an intermittent basis, which is an important consideration for [16] compared azithromycin, 250 mg/day, azithromycin, 600 reducing treatment costs of MAC lung disease. Azithromycin mg/day, and clarithromycin, 1000 mg/day (each combined with has little significant metabolism through the cytochrome P-450 ethambutol) in the treatment of disseminated MAC infection hepatic enzyme system, and therefore azithromycin has low in 246 HIV-infected patients. The azithromycin, 250 mg/day arm was discontinued early because clearance of bacteremia Overall, azithromycin appears to have some pharmacologic was lower than in the other 2 arms. After 24 weeks of therapy advantages over clarithromycin for long-term intermittent ad- and through the last follow-up visit, no significant differences ministration, which is why we initially chose azithromycin as were found in the likelihood of developmental 1 or 2 negative the basis for intermittent regimens to treat pulmonary MAC cultures, the likelihood of relapse, or the mortality rate between Azithromycin for MAC Lung Disease • CID 2001:32 (1 June) • 1551
patients receiving azithromycin (600 mg/day) versus clarith- worthy that the initial rifabutin doses, 300 mg/day or 600 mg romycin (1000 mg/day). None of the MAC isolates from pa- t.i.w., used in these studies were higher than are now generally tients who experienced relapse who had received azithromycin used (150 mg/day or 300 mg t.i.w.). As has also been observed were resistant in vitro to macrolides. In contrast to the study in previous studies having patients with MAC lung disease, by Ward et al. [15], the study by Dunne et al. [16] suggests there was no significant difference in outcome between patients that in combination with ethambutol, azithromycin, 600 mg/ who received rifampin versus those who received rifabutin [4, day, provided microbiologic efficacy in disseminated MAC dis- 5, 10, 19]. Recent studies of disseminated MAC infection in ease similar to that of clarithromycin.
AIDS patients suggest that rifabutin plus 2 companion drugs In our studies of patients with MAC lung disease, it is not (including a macrolide) does not increase the clearance of bac- likely that administration of an inadequate dose of azithro- teremia in these patients when compared with the 2 companion mycin was responsible for the difference in treatment outcome drugs alone [16, 20]. Such studies have not been done in pul- compared to CCRs. Serum levels were measured in patients in monary MAC disease. As is the case for azithromycin and regimen A and in general were у0.5 mg/mL, with a strong clarithromycin, there has not been a prospective head-to-head correlation between high serum levels and adverse side effects trial comparing rifabutin with rifampin in macrolide-contain- [17]. Similarly, the difference probably is not due to the choice ing regimens for MAC lung disease. Given the frequent adverse of companion medications in ACRs and CCRs. One possible events seen with rifabutin and the apparent lack of therapeutic explanation is that achievable blood levels exceeding the MIC advantage, it is difficult to enthusiastically endorse administra- for MAC can be obtained with clarithromycin, which may be tion of rifabutin rather than rifampin routinely.
important for treatment outcome [7, 10, 18]. This explanation Given the findings in this study, intermittent (t.i.w.) admin- is perhaps most persuasive for the outcomes in patients with istration should be the preferred method of administration for MAC bacteremia who were described by Ward et al. [15]. It is MAC lung disease treatment regimens that use azithromycin.
a less intuitively appealing explanation for a chronic process, In addition to the efficacy of this approach, there is a significant such as MAC lung disease, in which the pathogen and the potential cost reduction with intermittent t.i.w. administration.
treatment agent are both primarily intracellular. Another pos- Assuming an average-sized individual (70 kg) for dosing con- sibility is that clarithromycin is more active in vivo against MAC siderations, the yearly pharmacy acquisition cost at our hospital for a daily azithromycin, rifabutin, and ethambutol regimen is Overall, the differences in efficacy between ACRs and CCRs approximately $4400, compared with $2800 for the same 3 for treatment of MAC lung disease are relatively small (table drugs administered on a t.i.w. basis. In addition, if rifampin isused in place of rifabutin, the annual pharmacy acquisition cost 3) [10]. It is unclear why there was not a significant difference for the t.i.w. regimen is further reduced, to approximately in MAC disease response at 6 months between ACRs and CCRs, $2400. We have also had initial success with an intermittent but a significant difference at the end of therapy [4, 5]. It is (t.i.w.) CCR for treatment of MAC lung disease [21]. If this also unclear why the intermittent azithromycin regimen (reg- success is maintained, then intermittent therapy for MAC lung imen C) was the most effective azithromycin regimen. These disease would be preferable with both azithromycin- and clar- studies are relatively small, and in the absence of a large head- ithromycin-based treatment regimens.
to-head trial between ACRs and CCRs for treatment of MAClung disease, it is difficult to make definitive statements aboutthe superiority of one agent over the other for producing long- References
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