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Zithromax

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Zithromax

CLINICAL PHARMACOLOGY

Mechanism Of Action

Azithromycin is a macrolide antibacterial drug [see Microbiology].

Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was > 30 after one hour of incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.

Pharmacodynamics

Based on animal models of infection, the antibacterial activity of azithromycin appears to correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for certain pathogens (S. pneumoniae and S. aureus). The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with azithromycin.

Cardiac Electrophysiology

QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1000 mg) alone or in combination with oral azithromycin (500 mg, 1000 mg, and 1500 mg once daily). Coadministration of azithromycin increased the QTc interval in a dose-and concentration-dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.

Pharmacokinetics

The pharmacokinetic parameters of azithromycin in plasma after dosing as per labeled recommendations in healthy young adults and asymptomatic HIV-positive adults (age 18-40 years old) are portrayed in the following chart:

MEAN (CV%) PK PARAMETER

DOSE/DOSAGE FORM (serum, except as indicated) Subjects Day No. C'max ( mcg/mL) Tmax (hr) C24 (mcg/mL) AUC (mcg•hr/mL) T½ (hr) Urinary Excretion (% of dose)
500 mg/250 mg capsule 12 1 0.41 2.5 0.05 2.6a - 4.5
and 250 mg on Days 2-5 12 5 0.24 3.2 0.05 2.1a - 6.5
1200 mg/600 mg tablets %CV 12 1 0.66 (62%) 2.5 (79%) 0.074 (49%) 6.8b (64%) 40 (33%) -
600 mg tablet/day %CV 7 1 0.3325% 2.0 (50%) 0.039 (36%) 2.4a (19%)
%CV 7 22 0.55 (18%) 2.1 (52%) 0.14 (26%) 5.8a (25%) 84.5 --
600 mg tablet/day (leukocytes)%CV 7 22 252 (49%) 10.9 (28%) 146 (33%) 4763a (42%) 82.8- --
aAUC 0-24 ;
b0-last.

With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2-5, C min and C max remained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, azithromycin C min levels required 5 to 7 days to reach steady state.

In asymptomatic HIV-positive adult subjects receiving 600 mg ZITHROMAX tablets once daily for 22 days, steady state azithromycin serum levels were achieved by Day 15 of dosing.

The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues.

Absorption

The 1 gram single-dose packet is bioequivalent to four 250 mg azithromycin capsule

When the oral suspension of azithromycin was administered with food, the C max increased by 46% and the AUC by 14%.

The absolute bioavailability of two 600 mg tablets was 34% (CV=56%). Administration of two 600 mg tablets with food increased Cmax by 31% (CV=43%) while the extent of absorption (AUC) was unchanged (mean ratio of AUCs=1.00; CV=55%).

Distribution

The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 μg/mL to 7% at 2 μg/mL.

The antibacterial activity of azithromycin is pH related and appears to be reduced with decreasing pH. However, the extensive distribution of drug to tissues may be relevant to clinical activity.

Azithromycin has been shown to penetrate into tissues in humans, including skin, lung, tonsil, and cervix.. Extensive tissue distribution was confirmed by examination of additional tissues and fluids (bone, ejaculum, prostate, ovary, uterus, salpinx, stomach, liver, and gallbladder). As there are no data from adequate and well-controlled studies of azithromycin treatment of infections in these additional body sites, the clinical importance of these tissue concentration data is unknown.

Following oral administration of a single 1200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140 μg/mL. Concentrations remained above 32 μg/mL for approximately 60 hours. The mean half-lives for 6 males and 6 females were 34 hours and 57 hours, respectively. Leukocyte-to-plasma C max ratios for males and females were 258 (±77%) and 175 (±60%), respectively, and the AUC ratios were 804 (±31%) and 541 (±28%), respectively. The clinical relevance of these findings is unknown.

Following oral administration of multiple daily doses of 600 mg (1 tablet/day) to asymptomatic HIV-positive adults, mean maximum concentration in peripheral leukocytes was 252 μg/mL (±49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146 μg/mL (±33%). The mean leukocyte-to-serum C max ratio was 456 (±38%) and the mean leukocyte to serum AUC ratio was 816 (±31%). The clinical relevance of these findings is unknown.

Metabolism

In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.

Elimination

Plasma concentrations of azithromycin following single 500 mg oral and IV doses declined in a polyphasic pattern resulting in an average terminal half-life of 68 hours. Biliary excretion of azithromycin, predominantly as unchanged drug, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.

Specific Populations

Renal Insufficiency

Azithromycin pharmacokinetics was investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1.0 g dose of azithromycin (4 250 mg capsules), the mean C max and AUC 0-120 increased by 5.1% and 4.2%, respectively, in subjects with GFR 10 to 80 mL/min compared to subjects with normal renal function (GFR > 80 mL/min). The mean C max and AUC 0-120 increased 61% and 35%, respectively, in subjects with end-stage renal disease (GFR < 10 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min).

Hepatic Insufficiency

The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established.

Gender

There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended on the basis of gender.

Geriatric Patients

Pharmacokinetic parameters in older volunteers (65 to 85 years old) were similar to those in younger volunteers (18 to 40 years old) for the 5-day therapeutic regimen. Dosage adjustment does not appear to be necessary for older patients with normal renal and hepatic function receiving treatment with this dosage regimen [see Geriatric Use].

Pediatric Patients

For information regarding the pharmacokinetics of ZITHROMAX (azithromycin for oral suspension) in pediatric patients, see the prescribing information for ZITHROMAX (azithromycin for oral suspension) 100 mg/5 mL and 200 mg/5 mL bottles.

Drug-drug Interactions

Drug interaction studies were performed with azithromycin and other drugs likely to be co-administered. The effects of coadministration of azithromycin on the pharmacokinetics of other drugs are shown in Table 1 and the effects of other drugs on the pharmacokinetics of azithromycin are shown in Table 2.

Co-administration of azithromycin at therapeutic doses had a modest effect on the pharmacokinetics of the drugs listed in Table 1. No dosage adjustment of drugs listed in Table 1 is recommended when co-administered with azithromycin.

Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the C max and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2 [see DRUG INTERACTIONS].

Table 1: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin

Co-administered Drug Dose of Co-administered Drug Dose of Azithromycin n Ratio (with/without azithromycin) of Co-administered Drug Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Mean C max Mean AUC
Atorvastatin 10 mg/day for 8 days 500 mg/day orally on days 6-8 12 0.83
(0.63 to 1.08)
1.01
(0.81 to 1.25)
Carbamazepine 200 mg/day for 2 days, then 200 mg twice a day for 18 days 500 mg/day orally for days 16-18 7 0.97
(0.88 to 1.06)
0.96
(0.88 to 1.06)
Cetirizine 20 mg/day for 11 days 500 mg orally on day 7, then 250 mg/day on days 8-11 14 1.03
(0.93 to 1.14)
1.02
(0.92 to 1.13)
Didanosine 200 mg orally twice a day for 21 days 1,200 mg/day orally on days 8-21 6 1.44
(0.85 to 2.43)
1.14
(0.83 to 1.57)
Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.04* 0.95*
Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 1.04
(0.98 to 1.11)
1.01
(0.97 to 1.05)
Indinavir 800 mg three times a day for 5 days 1,200 mg orally on day 5 18 0.96
(0.86 to 1.08)
0.90
(0.81 to 1.00)
Midazolam 15 mg orally on day 3 500 mg/day orally for 3 days 12 1.27
(0.89 to 1.81)
1.26
(1.01 to 1.56)
Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 0.90
(0.81 to 1.01)
0.85
(0.78 to 0.93)
Sildenafil 100 mg on days 1 and 4 500 mg/day orally for 3 days 12 1.16
(0.86 to 1.57)
0.92
(0.75 to 1.12)
Theophylline 4 mg/kg IV on days 1, 11, 25 500 mg orally on day 7, 250 mg/day on days 8-11 10 1.19
(1.02 to 1.40)
1.02
(0.86 to 1.22)
Theophylline 300 mg orally BID x 15 days 500 mg orally on day 6, then 250 mg/day on days 7-10 8 1.09
(0.92 to 1.29)
1.08
(0.89 to 1.31)
Triazolam 0.125 mg on day 2 500 mg orally on day 1, then 250 mg/day on day 2 12 1.06* 1.02*
Trimethoprim/ Sulfamethoxazole 160 mg/800 mg/day orally for 7 days 1,200 mg orally on day 7 12 0.85
(0.75 to 0.97)/ 0.90
(0.78 to 1.03)
0.87
(0.80 to 0.95/ 0.96
(0.88 to 1.03)
Zidovudine 500 mg/day orally for 21 days 600 mg/day orally for 14 days 5 1.12
(0.42 to 3.02)
0.94
(0.52 to 1.70)
Zidovudine 500 mg/day orally for 21 days 1,200 mg/day orally for 14 days 4 1.31
(0.43 to 3.97)
1.30
(0.69 to 2.43)
* -90% Confidence interval not reported

Table 2: Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs [see DRUG INTERACTIONS].

Co-administered Drug Dose of Coadministered Drug Dose of Azithromycin n Ratio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Mean C max Mean AUC
Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.22
(1.04 to 1.42)
0.92*
Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 0.82
(0.66 to 1.02)
1.07
(0.94 to 1.22)
Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 2.36
(1.77 to 3.15)
2.12
(1.80 to 2.50)
* -90% Confidence interval not reported

Microbiology

Azithromycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in [see INDICATIONS AND USAGE].

Aerobic Gram-Positive Microorganisms

Staphylococcus aureus
Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

NOTE: Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains. Most strains of Enterococcus faecalis and methicillin-resistant staphylococci are resistant to azithromycin.

Aerobic Gram-Negative Microorganisms

Haemophilus influenzae
Moraxella catarrhalis

Other Microorganisms

Chlamydia trachomatis

Beta-lactamase production should have no effect on azithromycin activity.

Azithromycin has been shown to be active in vitro and in the prevention and treatment of disease caused by the following microorganisms:

Mycobacteria
Mycobacterium avium
complex (MAC) consisting of:
Mycobacterium avium

Mycobacterium intracellulare

The following in vitro data are available, but their clinical significance is unknown.

Azithromycin exhibits in vitro minimal inhibitory concentrations (MICs) of 2.0 μg/mL or less against most ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of azithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

Aerobic Gram-Positive Microorganisms

Streptococci (Groups C, F, G)
Viridans group streptococci

Aerobic Gram-Negative Microorganisms

Bordetella pertussis
Campylobacter jejuni

Haemophilus ducreyi

Legionella pneumophila

Anaerobic Microorganisms

Bacteroides bivius
Clostridium perfringens

Peptostreptococcus species

Other Microorganisms

Borrelia burgdorferi
Mycoplasma pneumoniae

Treponema pallidum

Ureaplasma urealyticum

Susceptibility Testing of Bacteria Excluding Mycobacteria

The in vitro potency of azithromycin is markedly affected by the pH of the microbiological growth medium during incubation. Incubation in a 10% CO 2 atmosphere will result in lowering of media pH (7.2 to 6.6) within 18 hours and in an apparent reduction of the in vitro potency of azithromycin. Thus, the initial pH of the growth medium should be 7.2-7.4, and the CO 2 content of the incubation atmosphere should be as low as practical.

Azithromycin can be solubilized for in vitro susceptibility testing by dissolving in a minimum amount of 95% ethanol and diluting to working concentration with water.

Dilution Techniques

Quantitative methods are used to determine minimal inhibitory concentrations that provide reproducible estimates of the susceptibility of bacteria to antibacterial compounds. One such standardized procedure uses a standardized dilution method1 (broth, agar or microdilution) or equivalent with azithromycin powder. The MIC values should be interpreted according to the following criteria:

MIC (μg/mL) Interpretation
< 2 Susceptible (S)
4 Intermediate (I)
> 8 Resistant (R)

A report of “Susceptible” indicates that the pathogen is likely to respond to monotherapy with azithromycin. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that usually achievable drug concentrations are unlikely to be inhibitory and that other therapy should be selected.

Measurement of MIC or minimum bacterial concentration (MBC) and achieved antibacterial compound concentrations may be appropriate to guide therapy in some infections. [see CLINICAL PHARMACOLOGY] section for further information on drug concentrations achieved in infected body sites and other pharmacokinetic properties of this antibacterial drug product.)

Standardized susceptibility test procedures require the use of laboratory control microorganisms. Standard azithromycin powder should provide the following MIC values:

Microorganism MIC (μg/mL)
Escherichia coli ATCC 25922 2.0-8.0
Enterococcus faecalis ATCC 29212 1.0-4.0
Staphylococcus aureus ATCC 29213 0.25-1.0

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antibacterial compounds. One such standardized procedure2 that has been recommended for use with disks to test the susceptibility of microorganisms to azithromycin uses the 15 μg azithromycin disk. Interpretation involves the correlation of the diameter obtained in the disk test with the MIC for azithromycin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 μg azithromycin disk should be interpreted according to the following criteria:

Zone Diameter (mm) Interpretation
≥ 18 Susceptible(S)
14-17 Intermediate(I)
≤ 13 Resistant(R)

Interpretation should be as stated above for results using dilution techniques.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms. The 15 μg azithromycin disk should provide the following zone diameters in these laboratory test quality control strains:

Microorganism Zone Diameter (mm)
Staphylococcus aureus ATCC 25923 21-26

In Vitro Activity of Azithromycin Against Mycobacteria

Azithromycin has demonstrated in vitro activity against MAC organisms. While gene probe techniques may be used to distinguish between M. avium and M. intracellulare, many studies only reported results on MAC isolates. Azithromycin has also been shown to be active against phagocytized MAC organisms in mouse and human macrophage cell cultures as well as in the beige mouse infection model.

Various in vitro methodologies employing broth or solid media at different pHs, with and without oleic acid-albumindextrose-catalase (OADC), have been used to determine azithromycin MIC values for MAC strains. In general, azithromycin MIC values decreased 4-8 fold as the pH of Middlebrook 7H11 agar media increased from 6.6 to 7.4. At pH 7.4, azithromycin MIC values determined with Mueller-Hinton agar were 4 fold higher than that observed with Middlebrook 7H12 media at the same pH. Utilization of oleic OADC in these assays has been shown to further alter MIC values. The relationship between azithromycin and clarithromycin MIC values has not been established. In general, azithromycin MIC values were observed to be 2-32 fold higher than clarithromycin independent of the susceptibility method employed.

The ability to correlate MIC values and plasma drug levels is difficult as azithromycin concentrates in macrophages and tissues. [see CLINICAL PHARMACOLOGY]

Drug Resistance

Complete cross-resistance between azithromycin and clarithromycin has been observed with MAC isolates. In most isolates, a single-point mutation at a position that is homologous to the Escherichia coli positions 2058 or 2059 on the 23S rRNA gene is the mechanism producing this cross-resistance pattern.3,4 MAC isolates exhibiting cross-resistance show an increase in azithromycin MICs to ≥ 128 μg/mL with clarithromycin MICs increasing to ≥ 32 μg/mL. These MIC values were determined employing the radiometric broth dilution susceptibility testing method with Middlebrook 7H12 medium. The clinical significance of azithromycin and clarithromycin cross-resistance is not fully understood at this time but preclinical data suggest that reduced activity to both agents will occur after MAC strains produce the 23S rRNA mutation.

Susceptibility Testing for MAC

The disk diffusion techniques and dilution methods for susceptibility testing against gram-positive and gram-negative bacteria should not be used for determining azithromycin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining MIC values against MAC organisms have not been standardized or validated. Azithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of media, and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant to azithromycin have not been established.

The clinical relevance of azithromycin in vitro susceptibility test results for other mycobacterial species, including Mycobacterium tuberculosis, using any susceptibility testing method has not been determined.

Animal Toxicology

Phospholipidosis (intracellular phospholipid accumulation) has been observed in some tissues of mice, rats, and dogs given multiple doses of azithromycin. It has been demonstrated in numerous organ systems (e.g., eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) in dogs and rats treated with azithromycin at doses which, expressed on the basis of body surface area, are similar to or less than the highest recommended adult human dose. This effect has been shown to be reversible after cessation of azithromycin treatment. Based on the pharmacokinetic data, phospholipidosis has been seen in the rat (50 mg/kg/day dose) at the observed maximal plasma concentration of 1.3 μg/mL (1.6 times the observed Cmax of 0.821 μg/mL at the adult dose of 2 g.) Similarly, it has been shown in the dog (10 mg/kg/day dose) at the observed maximal serum concentration of 1 μg/mL (1.2 times the observed Cmax of 0.821 μg/mL at the adult dose of 2 g). Phospholipidosis was also observed in neonatal rats dosed for 18 days at 30 mg/kg/day, which is less than the pediatric dose of 60 mg/kg based on body surface area. It was not observed in neonatal rats treated for 10 days at 40 mg/kg/day with mean maximal serum concentrations of 1.86 μg/ml, approximately 1.5 times the Cmax of 1.27 μg/ml at the pediatric dose. Phospholipidosis has been observed in neonatal dogs (10 mg/kg/day) at maximum mean whole blood concentrations of 3.54 μg/ml, approximately 3 times the pediatric dose Cmax. The significance of the finding for animals and for humans is unknown.

Clinical Studies

Clinical Studies In Patients With Advanced HIV Infection For The Prevention And Treatment Of Disease Due To Disseminated MAC

[see INDICATIONS AND USAGE]

Prevention of Disseminated MAC Disease

Two randomized, double-blind clinical trials were performed in patients with CD4 counts < 100 cells/μL. The first trial (Study 155) compared azithromycin (1200 mg once weekly) to placebo and enrolled 182 patients with a mean CD4 count of 35 cells/mcgL. The second trial (Study 174) randomized 723 patients to either azithromycin (1200 mg once weekly), rifabutin (300 mg daily), or the combination of both. The mean CD4 count was 51 cells/mcgL. The primary endpoint in these trials was disseminated MAC disease. Other endpoints included the incidence of clinically significant MAC disease and discontinuations from therapy for drug-related side effects.

MAC bacteremia

In Study 155, 85 patients randomized to receive azithromycin and 89 patients randomized to receive placebo met the entrance criteria. Cumulative incidences at 6, 12, and 18 months of the possible outcomes are in the following table:

Cumulative Incidence Rate, %: Placebo (n=89)
Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up
6 69.7 13.5 6.7 10.1
12 47.2 19.1 15.7 18.0
18 37.1 22.5 18.0 22.5
Cumulative Incidence Rate, %: Azithromycin (n=85)
Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up
6 84.7 3.5 9.4 2.4
12 63.5 8.2 16.5 11.8
18 44.7 11.8 25.9 17.6

The difference in the one-year cumulative incidence rates of disseminated MAC disease (placebo – azithromycin) is 10.9%. This difference is statistically significant (p=0.037) with a 95% confidence interval for this difference of 0.8%, 20.9%. The comparable number of patients experiencing adverse events and the fewer number of patients lost to follow-up on azithromycin should be taken into account when interpreting the significance of this difference.

In Study 174, 223 patients randomized to receive rifabutin, 223 patients randomized to receive azithromycin, and 218 patients randomized to receive both rifabutin and azithromycin met the entrance criteria. Cumulative incidences at 6, 12, and 18 months of the possible outcomes are recorded in the following table:

>
Cumulative Incidence Rate, %: Rifabutin (n=223)
Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up
6 83.4 7.2 8.1 1.3
12 60.1 15.2 16.1 8.5
18 40.8 21.5 24.2 13.5
Cumulative Incidence Rate, %: Azithromycin (n=223)
Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up
6 85.2 3.6 5.8 5.4
12 65.5 7.6 16.1 10.8
18 45.3 12.1 23.8 18.8
Cumulative Incidence Rate, %: Azithromycin/Rifabutin Combination (n=218)
Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up
6 89.4 1.8 5.5 3.2
12 71.6 2.8 15.1 10.6
18 49.1 6.4 29.4 15.1

Comparing the cumulative one-year incidence rates, azithromycin monotherapy is at least as effective as rifabutin monotherapy. The difference (rifabutin – azithromycin) in the one-year rates (7.6%) is statistically significant (p=0.022) with an adjusted 95% confidence interval (0.9%, 14.3%). Additionally, azithromycin/rifabutin combination therapy is more effective than rifabutin alone. The difference (rifabutin – azithromycin/rifabutin) in the cumulative one-year incidence rates (12.5%) is statistically significant (p < 0.001) with an adjusted 95% confidence interval of 6.6%, 18.4%. The comparable number of patients experiencing adverse events and the fewer number of patients lost to follow-up on rifabutin should be taken into account when interpreting the significance of this difference.

In Study 174, sensitivity testing5 was performed on all available MAC isolates from subjects randomized to either azithromycin, rifabutin, or the combination. The distribution of MIC values for azithromycin from susceptibility testing of the breakthrough isolates was similar between trial arms. As the efficacy of azithromycin in the treatment of disseminated MAC has not been established, the clinical relevance of these in vitro MICs as an indicator of susceptibility or resistance is not known.

Clinically Significant Disseminated MAC Disease

In association with the decreased incidence of bacteremia, patients in the groups randomized to either azithromycin alone or azithromycin in combination with rifabutin showed reductions in the signs and symptoms of disseminated MAC disease, including fever or night sweats, weight loss, and anemia.

Discontinuations from Therapy for Drug-Related Side Effects

In Study 155, discontinuations for drug-related toxicity occurred in 8.2% of subjects treated with azithromycin and 2.3% of those given placebo (p=0.121). In Study 174, more subjects discontinued from the combination of azithromycin and rifabutin (22.7%) than from azithromycin alone (13.5%; p=0.026) or rifabutin alone (15.9%; p=0.209).

Safety

As these patients with advanced HIV disease were taking multiple concomitant medications and experienced a variety of intercurrent illnesses, it was often difficult to attribute adverse reactions to study medication. Overall, the nature of adverse reactions seen on the weekly dosage regimen of azithromycin over a period of approximately one year in patients with advanced HIV disease were similar to that previously reported for shorter course therapies.

INCIDENCE OF ONE OR MORE TREATMENT-RELATEDa ADVERSE REACTIONSb IN HIV INFECTED PATIENTS RECEIVING PROPHYLAXIS FOR DISSEMINATED MAC OVER APPROXIMATELY 1 YEAR

  Study 155 Study 174
Placebo
(N=91)
Azithromycin 1200 mg weekly
(N=89)
Azithromycin 1200 mg weekly
(N=233)
Rifabutin 300 mg daily
(N=236)
Azithromycin + Rifabutin
(N=224)
Mean Duration of Therapy (days) 303.8 402.9 315 296.1 344.4
Discontinuation of Therapy 2.3 8.2 13.5 15.9 22.7
Autonomic Nervous System
  Mouth Dry 0 0 0 3.0 2.7
Central Nervous System
  Dizziness 0 1.1 3.9 1.7 0.4
  Headache 0 0 3.0 5.5 4.5
Gastrointestinal
  Diarrhea 15.4 52.8 50.2 19.1 50.9
  Loose Stools 6.6 19.1 12.9 3.0 9.4
  Abdominal Pain 6.6 27 32.2 12.3 31.7
  Dyspepsia 1.1 9 4.7 1.7 1.8
  Flatulence 4.4 9 10.7 5.1 5.8
  Nausea 11 32.6 27.0 16.5 28.1
  Vomiting 1.1 6.7 9.0 3.8 5.8
General
  Fever 1.1 0 2.1 4.2 4.9
  Fatigue 0 2.2 3.9 2.1 3.1
  Malaise 0 1.1 0.4 0 2.2
Musculoskeletal
  Arthralgia 0 0 3.0 4.2 7.1
Psychiatric
  Anorexia 1.1 0 2.1 2.1 3.1
Skin & Appendages
  Pruritus 3.3 0 3.9 3.4 7.6
  Rash 3.2 3.4 8.1 9.4 11.1
  Skin discoloration 0 0 0 2.1 2.2
Special Senses
  Tinnitus 4.4 3.4 0.9 1.3 0.9
  Hearing Decreased 2.2 1.1 0.9 0.4 0
  Uveitis 0 0 0.4 1.3 1.8
  Taste Perversion 0 0 1.3 2.5 1.3
aIncludes those reactions considered possibly or probably related to study drug
b > 2% adverse reaction rates for any group (except uveitis)

Adverse reactions related to the gastrointestinal tract were seen more frequently in patients receiving azithromycin than in those receiving placebo or rifabutin. In Study 174, 86% of diarrheal episodes were mild to moderate in nature with discontinuation of therapy for this reason occurring in only 9/233 (3.8%) of patients.

Changes in Laboratory Values

In these immunocompromised patients with advanced HIV infection, it was necessary to assess laboratory abnormalities developing on trial with additional criteria if baseline values were outside the relevant normal range.

PROPHYLAXIS AGAINST DISSEMINATED MAC ABNORMAL LABORATORY VALUESa

  Placebo Azithromycin 1200 mg weekly Rifabutin 300 mg daily Azithromycin & Rifabutin
Hemoglobin < 8 g/dL 1/51 2% 4/170 2% 4/114 4% 8/107 8%
Platelet Count < 50 x 103/mm³ 1/71 1% 4/260 2% 2/182 1% 6/181 3%
WBC Count < 1 x 103/mm³ 0/8 0% 2/70 3% 2/47 4% 0/43 0%
Neutrophils < 500/mm³ 0/26 0% 4/106 4% 3/82 4% 2/78 3%
SGOT > 5 x ULNb 1/41 2% 8/158 5% 3/121 3% 6/114 5%
SGPT > 5 x ULN 0/49 0% 8/166 5% 3/130 2% 5/117 4%
Alk Phos > 5 x ULN 1/80 1% 4/247 2% 2/172 1% 3/164 2%
aexcludes subjects outside of the relevant normal range at baseline
bUpper Limit of Normal

Treatment of Disseminated MAC Disease

One randomized, double-blind clinical trial (Study 189) was performed in patients with disseminated MAC. In this trial, 246 HIV-infected patients with disseminated MAC received either azithromycin 250 mg daily (N=65), azithromycin 600 mg daily (N=91), or clarithromycin 500 mg twice a day (N=90), each administered with ethambutol 15 mg/kg daily, for 24 weeks. Blood cultures and clinical assessments were performed every 3 weeks through week 12 and monthly thereafter through week 24. After week 24, patients were switched to any open-label therapy at the discretion of the investigator and followed every 3 months through the last follow-up visit of the trial. Patients were followed from the baseline visit for a period of up to 3.7 years (median: 9 months). MAC isolates recovered during treatment or post-treatment were obtained whenever possible.

The primary endpoint was sterilization by week 24. Sterilization was based on data from the central laboratory, and was defined as two consecutive observed negative blood cultures for MAC, independent of missing culture data between the two negative observations. Analyses were performed on all randomized patients who had a positive baseline culture for MAC.

The azithromycin 250 mg arm was discontinued after an interim analysis at 12 weeks showed a significantly lower clearance of bacteremia compared to clarithromycin 500 mg twice a day. Efficacy results for the azithromycin 600 mg daily and clarithromycin 500 mg twice a day treatment regimens are described in the following table:

RESPONSE TO THERAPY OF PATIENTS TAKING ETHAMBUTOL AND EITHER AZITHROMYCIN 600 MG DAILY OR CLARITHROMYCIN 500 MG TWICE A DAY

  Azithromycin 600 mg daily Clarithromycin 500 mg twice a day a95.1% CI on difference
Patients with positive culture at baseline 68 57  
Week 24
  Two consecutive negative blood culturesb 31/68 (46%) 32/57 (56%) [-28, 7]
  Mortality 16/68 (24%) 15/57 (26%) [-18, 13]
a[95% confidence interval] on difference in rates (azithromycin-clarithromycin)
bPrimary endpoint

The primary endpoint, rate of sterilization of blood cultures (two consecutive negative cultures) at 24 weeks, was lower in the azithromycin 600 mg daily group than in the clarithromycin 500 mg twice a day group.

Sterilization by Baseline Colony Count

Within both treatment groups, the sterilization rates at week 24 decreased as the range of MAC cfu/mL increased.

  Azithromycin 600 mg
(N=68)
Clarithromycin 500 mg twice a day
(N=57)
groups stratified by MAC colony counts at baseline no. (%) subjects in stratified group sterile at week 24 no. (%) subjects in stratified group sterile at week 24
≤ 10 cfu/mL 10/15 (66.7%) 12/17 (70.6%)
11-100 cfu/mL 13/28 (46.4%) 13/19 (68.4%)
101-1,000 cfu/mL 7/19 (36.8%) 5/13 (38.5%)
1,001-10,000 cfu/mL 1/5 (20.0%) 1/5 (20%)
> 10,000 cfu/mL 0/1 (0.0%) 1/3 (33.3%)

Susceptibility Pattern of MAC Isolates

Susceptibility testing was performed on MAC isolates recovered at baseline, at the time of breakthrough on therapy or during post-therapy follow-up. The T100 radiometric broth method was employed to determine azithromycin and clarithromycin MIC values. Azithromycin MIC values ranged from < 4 to > 256 μg/mL and clarithromycin MICs ranged from < 1 to > 32 μg/mL. The individual MAC susceptibility results demonstrated that azithromycin MIC values could be 4 to 32-fold higher than clarithromycin MIC values.

During treatment and post-treatment follow-up for up to 3.7 years (median: 9 months) in Study 189, a total of 6/68 (9%) and 6/57 (11%) of the patients randomized to azithromycin 600 mg daily and clarithromycin 500 mg twice a day respectively, developed MAC blood culture isolates that had a sharp increase in MIC values. All twelve MAC isolates had azithromycin MICs ≥ 256 μg/mL and clarithromycin MICs > 32 μg/mL. These high MIC values suggest development of drug resistance. However, at this time, specific breakpoints for separating susceptible and resistant MAC isolates have not been established for either macrolide.

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

3. Dunne MW, Foulds G, Retsema JA. Rationale for the use of azithromycin as Mycobacterium avium chemoprophylaxis. Am J Med 1997; 102(5C):37-49.

4. Meier A, Kirshner P, Springer B, et al. Identification of mutations in 23S rRNA gene of clarithromycin-resistant Mycobacterium intracellulare. Antimicrob Agents Chemother. 1994; 38:381-384.

5. Methodology per Inderlied CB, et al. Determination of In Vitro Susceptibility of Mycobacterium avium Complex Isolates to Antimicrobial Agents by Various Methods. Antimicrob Agents Chemother. 1987; 31:1697-1702.

Last reviewed on RxList: 6/23/2014
This monograph has been modified to include the generic and brand name in many instances.

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