Azithromycin (Page 5 of 6)

12.4 Microbiology

Mechanism of Action

Azithromycin acts by binding to the 23S rRNA of the 50S ribosomal subunit of susceptible microorganisms inhibiting bacterial protein synthesis and impeding the assembly of the 50S ribosomal subunit.

Resistance

The most frequently encountered mechanism of resistance to azithromycin is modification of the 23S rRNA target, most often by methylation. Ribosomal modifications can determine cross resistance to other macrolides, lincosamides, and streptogramin B (MLS B phenotype). The mechanism of acquired mutational resistance in isolates of Mycobacterium avium complex (i.e., 23S rRNA genemutation) is the same for both clarithromycin and azithromycin.

Antimicrobial Activity

Azithromycin has been shown to be active against the following microorganisms, both in vitro and in clinical infections. [see Indications and Usage ( 1)]

Mycobacteria

Mycobacterium avium complex (MAC) consisting of:

Mycobacterium avium

Mycobacterium intracellulare

Other Microorganisms

Chlamydia trachomatis

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human lymphocyte clastogenic assay, and mouse bone marrow clastogenic assay. In fertility studies conducted in male and female rats, oral administration of azithromycin for 64 to 66 days (males) or 15 days (females) prior to and during cohabitation resulted in decreased pregnancy rate at 20 and 30 mg/kg/day when both males and females were treated with azithromycin. This minimal effect on pregnancy rate (approximately 12% reduction compared to concurrent controls) did not become more pronounced when the dose was increased from 20 to 30 mg/kg/day (approximately 0.3 to 0.5 times the adult human daily dose of 600 mg based on body surface area) and it was not observed when only one animal in the mated pair was treated. There were no effects on any other reproductive parameters, and there were no effects on fertility at 10 mg/kg/day. The relevance of these findings to patients being treated with azithromycin at the doses and durations recommended in the prescribing information is uncertain.

13.2 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 mcg/mL (1.6 times the observed C max of 0.821 mcg/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 mcg/mL (1.2 times the observed C max of 0.821 mcg/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 the 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 mcg/mL, approximately 1.5 times the C max of 1.27 mcg/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 mcg/mL, approximately 3 times the pediatric dose C max .

The significance of the finding for animals and for humans is unknown.

14 CLINICAL STUDIES

14.1 Clinical Studies in Patients with Advanced HIV Infection for the Prevention and Treatment of Disease Due to Disseminated Mycobacterium avium Complex (MAC)

[see Indications and Usage ( 1)]

Prevention of Disseminated MAC Disease

Two randomized, double blind clinical trials were performed in patients with CD4 counts < 100 cells/mcL. The first trial (Study 155) compared azithromycin (1,200 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 (1,200 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)
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 testing 1 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-RELATED * ADVERSE REACTIONS IN HIV INFECTED PATIENTS RECEIVING PROPHYLAXIS FOR DISSEMINATED MAC OVER APPROXIMATELY 1 YEAR
*
Includes those reactions considered possibly or probably related to study drug
> 2% adverse reaction rates for any group (except uveitis)
Study 155 Study 174

Placebo

(N = 91)

Azithromycin 1,200 mg weekly

(N = 89)

Azithromycin 1,200 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

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 VALUES *
*
excludes subjects outside of the relevant normal range at baseline
Upper Limit of Normal
Placebo Azithromycin 1,200 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 × 10 3 /mm 3 1/71 1% 4/260 2% 2/182 1% 6/181 3%
WBC Count < 1 × 10 3 /mm 3 0/8 0% 2/70 3% 2/47 4% 0/43 0%
Neutrophils < 500/mm 3 0/26 0% 4/106 4% 3/82 4% 2/78 3%
SGOT > 5 × ULN 1/41 2% 8/158 5% 3/121 3% 6/114 5%
SGPT > 5 × ULN 0/49 0% 8/166 5% 3/130 2% 5/117 4%
Alk Phos > 5 × ULN 1/80 1% 4/247 2% 2/172 1% 3/164 2%

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
*
[95% confidence interval] on difference in rates (azithromycin-clarithromycin)
Primary endpoint
Azithromycin

600 mg daily

Clarithromycin 500 mg twice a day *95.1% CI on difference
Patients with positive culture at baseline 68
57
Week 24
Two consecutive negative blood cultures 31/68 (46%) 32/57 (56%)
[-28, 7]
Mortality 16/68 (24%) 15/57 (26%) [-18, 13]

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 to 100 cfu/mL 13/28 (46.4%) 13/19 (68.4%)
101 to 1,000 cfu/mL 7/19 (36.8%) 5/13 (38.5%)
1,001 to 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 mcg/mL and clarithromycin MICs ranged from < 1 to > 32 mcg/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 mcg/mL and clarithromycin MICs > 32 mcg/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.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2022. All Rights Reserved.