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Zithromax (azithromycin) drug information: dosage, unwanted side effects, drug interactions and user
Pharmacokinetics

Following oral administration, azithromycin is rapidly
absorbed and widely distributed through the entire body. Rapid distribution of azithromycin
into tissues and high concentration within cells lead to significantly higher
azithromycin concentrations in tissues in comparison to plasma or serum. The 1 g single
dose packet is bioequivalent to four 250 mg azithromycin capsules.

The pharmacokinetic parameters of azithromycin in plasma after dosing according to labeled recommendations in healthy the younger generation and asymptomatic HIV-seropositive adults (age 18-40 yrs . old) are portrayed within the following chart:

MEAN (CV%) PK PARAMETER

DOSE/DOSAGE FORM (serum, except as indicated)
Subjects
Day No. Cmax

(µg/mL)
Tmax (hr)
C24

(µg/mL)
AUC (µg•hr/mL)
T½ (hr)
Urinary Excretion (% of dose)
500 mg/250 mg capsule
12
Day 1
0. 41
2. 5
0. 05
2. 6a
-
4. 5
and 250 mg on Days 2-5
12
Day 5
0. 24
3. 2
0. 05
2. 1a
-
6. 5
1200 mg/600 mg tablets
12
Day 1
0. 66
2. 5
0. 074
6. 8b
40
-
% CV
(62%)
(79%)
(49%)
(64%)
(33%)
600 mg tablet/day
7
1
0. 33
2. 0
0. 039
2 4a
% CV
25%
(50%)
(36%)
(19%)
7
22
0. 55
2. 1
0. 14
5. 8a
84. 5
-
% CV
(18%)
(52%)
(26%)
(25%)
-
600 mg tablet/day (leukocytes)
7
22
252
10. 9
146
4763a
82. 8
-
% CV
(49%)
(28%)
(33%)
(42%)
-
-
a AUC0-24; b
0-last.

In these studies (500 mg Day 1, 250 mg Days 2-5), there were no significant
difference inside the disposition of azithromycin between female and male subjects. Plasma concentrations of azithromycin following single 500 mg oral we. V. doses declined inside a polyphasic pattern resulting in a typical terminal half-life
of 68 hours. With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2-5, Cmax
and Cmax remained essentially unchanged from Day 2 through Day 5 of therapy. However, with out a loading dose, azithromycin Cmax levels required 6 or 7 days
to arrive at steady-state.

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

When azithromycin capsules were administered with food, the interest rate of absorption (Cmax) of azithromycin was reduced by 52% as well as the extent of absorption (AUC) by 43%.

When the oral suspension of azithromycin was administered with food, the Cmax increased by 46% along with 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%) whilst the extent of absorption (AUC) was unchanged (mean ratio of AUCs=1. 00; CV=55%).

The AUC of azithromycin in 250 mg capsules was unaffected by coadministration of your antacid containing aluminum and magnesium hydroxide with ZITHROMAX (azithromycin); however, the Cmax was reduced by 24%. Administration of cimetidine (800 mg) two hours prior to azithromycin had no relation to azithromycin absorption.

When studied in healthy elderly subjects from age 65 to 85 years, the pharmacokinetic parameters of azithromycin (500 mg Day 1, 250 mg Days 2-5) in elderly men were comparable to those invoved with youngsters; however, in elderly women, although higher peak concentrations (increased by 30 to 50%) were observed, no significant accumulation occurred.

The high values in adults for apparent steady-state variety of distribution (31. 1 L/kg) and plasma clearance (630 mL/min) declare that the prolonged half-life is due to extensive uptake and subsequent relieve drug from tissues. Selected tissue (or fluid) concentration and tissue (or fluid) to plasma/serum concentration ratios are shown inside the following table:

AZITHROMYCIN CONCENTRATIONS FOLLOWING TWO 250 mg (500 mg)
CAPSULES IN ADULTS

TISSUE OR FLUID
TIME AFTER DOSE (h)
TISSUE OR FLUID CONCENTRATION (µg/g or (µg/mL)1
CORRESPONDING PLASMA OR SERUM LEVEL (µg/mL)
TISSUE (FLUID) PLASMA (SERUM) RATIO1
SKIN
72-96
0. 4
0. 012
35
LUNG
72-96
4. 0
0. 012
> 100
SPUTUM*
2-4
1. 0
0. 64
2
SPUTUM**
10-12
2. 9
0. 1
30
TONSIL***
9-18
4. 5
0. 03
> 100
TONSIL***
180
0. 9
0. 006
> 100
CERVIX****
19
2. 8
0. 04
70
1 High tissue concentrations really should not be interpreted
being quantitatively linked to clinical efficacy. The antimicrobial activity
of azithromycin is pH related. Azithromycin concentrates in cell lysosomes
who have a low intraorganelle pH, of which the drug's activity is reduced. However, the extensive distribution of drug to tissues can be strongly related
clinical activity.

* Sample was obtained 2-4 hours following first dose

** Sample was obtained 10-12 hours following the first dose.

*** Dosing regimen of 2 doses of 250 mg each, separated by 12 hours.

**** Sample was obtained 19 hours from a single 500 mg dose.

The 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 therapy for infections within these additional body sites, the clinical significance of those tissue concentration details are unknown.

Following a regimen of 500 mg for the first day and 250 mg daily for 4 days, only small concentrations were noted in cerebrospinal fluid (less than 0. 01 µg/mL) from the presence of non-inflamed meninges.

Following oral administration of merely one 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 hr. The mean
half-lives for six males and 6 females were 34 hr and 57 hr, respectively. Leukocyte
to plasma Cmax ratios males and females were 258 (77%) and 175 (60%),
respectively, as well as 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-seropositive 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 Cmax ratio was 456 (38%) along with the mean leukocyte to
serum AUC ratio was 816 (31%). The clinical relevance of such findings
is unknown.

The serum protein binding of azithromycin is variable inside the concentration
range approximating human exposure, decreasing from 51% at 0. 02 µg/mL
to 7% at 2 µg/mL. Biliary excretion of azithromycin, predominantly as
unchanged drug, is usually a major route of elimination. Throughout every week,
approximately 6% on the administered dose sounds like unchanged drug in urine.

Renal Insufficiency

Azithromycin pharmacokinetics was investigated in 42 adults (21 to 85 years
of age) with varying examples of renal impairment. Following the oral administration
of a single 1. 0 g dose of azithromycin (4 x 250 mg capsules), the mean Cmax
and AUC0-120 increased by 5. 1% and 4. 2%, respectively in subjects
with GFR 10 to 80 mL/min in comparison to subjects with normal renal function (GFR
> 80 mL/min). The mean Cmax and AUC0-120 increased 61% and 35%,
respectively in subjects with end-stage renal disease (GFR 80 mL/min). (See DOSAGE AND
ADMINISTRATION. )

Hepatic Insufficiency

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

The effect of azithromycin within the plasma levels or pharmacokinetics of theophylline
administered in multiple doses adequate to arrive at therapeutic steady-state plasma
levels will not be known. (See PRECAUTIONS. )

Mechanism of Action: Azithromycin acts by binding to your 50S ribosomal
subunit of susceptible microorganisms and, thus, disturbing microbial
protein synthesis. Nucleic acid synthesis will not be affected.

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 60 minutes incubation. In vivo studies advise that concentration in phagocytes may contribute
to drug distribution to inflamed tissues.

Microbiology

Azithromycin is shown to be active against most strains in the following
microorganisms, in both vitro as well as in clinical infections as described
inside INDICATIONS section.

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 not have any relation to azithromycin activity.

Azithromycin is shown to be active in vitro plus the prevention
and treating disease attributable to these microorganisms:

Mycobacteria

Mycobacterium avium complex (MAC) composed of:

Mycobacterium avium

Mycobacterium intracellulare.

The following in vitro data are offered, however their clinical significance
is unknown.

Azithromycin exhibits in vitro minimal inhibitory concentrations (MICs)
of 2. 0 µg/mL or less against most ( ≥ 90%) strains in the following microorganisms;
however, the safety and effectiveness of azithromycin for treating clinical infections
because of these microorganisms are not 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 suffering from the pH
of the microbiological growth medium during incubation. Incubation in a 10%
COi atmosphere will result in cut in media pH (7. 2 in order to six. 6) within 18 hours
plus an apparent lowering of the in vitro potency of azithromycin. Thus, your initial pH in the growth medium should be 7. 2-7. 4, and also the CO2
content of the incubation atmosphere must be only practical.

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

Dilution Techniques

Quantitative methods are utilized to determine minimal inhibitory concentrations
offering reproducible estimates from the susceptibility of bacteria to antimicrobial
compounds. One standardized procedure relies on 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" signifies that the pathogen will probably respond to monotherapy with azithromycin. A study of "Intermediate" indicates that the results should be thought about equivocal, and, when the microorganism is not fully vulnerable to alternative, clinically feasible drugs, test should be repeated. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. An investigation of "Resistant" indicates that usually achievable drug concentrations are unlikely being inhibitory which other therapy needs to be selected.

Measurement of MIC or MBC and achieved antimicrobial compound concentrations
may be appropriate to guide therapy in certain infections. (See CLINICAL PHARMACOLOGY
section for even more facts about drug concentrations achieved in infected
body sites along with pharmacokinetic properties of this antimicrobial drug product. )

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

Microorganism
MIC (µg/rnL)
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 which need measurement of zone diameters in addition provide
reproducible estimates on the susceptibility of bacteria to antimicrobial compounds. One particular standardized procedure2 that was recommended for use
with disks to check the susceptibility of microorganisms to azithromycin uses
the 15-lg azithromycin disk. Interpretation necessitates the correlation of the
diameter obtained in the disk test while using minimal inhibitory concentration
(MIC) for azithromycin.

Reports in the laboratory providing upshot of the conventional single-disk susceptibility test having a 15 µg azithromycin disk needs to be interpreted in line with the following criteria:

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

Interpretation needs to be as mentioned above for results using dilution techniques.

As with standardized dilution techniques, diffusion methods require by using laboratory control microorganisms. The 15-µg azithromycin disk has most likely furnished the next zone diameters over 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 revealed in vitro activity against Mycobacterium
avium complex (MAC) organisms. While gene probe techniques is known to
separate M. avium and M. intracellulare, many studies
only reported results on M. avium complex (MAC) isolates. Azithromycin
has been demonstrated that they are active against phagocytized M. avium complex
(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-albumin dextrose-catalase (OADC), are actually
employed to determine azithromycin MIC values for Mycobacterium avium complex
strains. On the whole, azithromycin MIC values decreased 4 to eight fold because 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 over that
observed with Middlebrook 7H12 media on the same pH. Make use of oleic acid-albumin-dextrose-catalase
(OADC) of these assays has been shown to further alter MIC values. The connection
between azithromycin and clarithromycin MIC values has not been established. Generally speaking, azithromycin MIC values were observed being 2 to 32 fold higher
than clarithromycin independent of the susceptibility method employed.

The ability to correlate MIC values and plasma drug levels is hard as
azithromycin concentrates in macrophages and tissues. (See CLINICAL PHARMACOLOGY)

Drug Resistance

Complete cross-resistance between azithromycin and clarithromycin has become
observed with Mycobacterium avium complex (MAC) isolates. In many isolates,
an individual point mutation at the position that is homologous for the Escherichia
coli positions 2058 or 2059 for the 23S rRNA gene is the mechanism producing
this cross-resistance pattern. 3,4 Mycobacterium avium complex
(MAC) isolates exhibiting cross-resistance show a rise 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 will not be fully understood at the moment but
preclinical data suggest that reduced activity to both agents will occur after
M. avium complex strains produce the 23S rRNA mutation.

Susceptibility testing for Mycobacterium avium complex (MAC)

The disk diffusion techniques and dilution techniques for susceptibility testing
against Gram-positive and Gram-negative bacteria really should not be employed for determining
azithromycin MIC values against mycobacteria. In vitro susceptibility
testing methods and diagnostic products currently available for determining
minimal inhibitory concentration (MIC) values against Mycobacterium avium
complex (MAC) organisms haven't been standardized or validated. Azithromycin
MIC values will vary with respect to the susceptibility testing method employed,
composition and pH of media and also the using supplements. Breakpoints to find out whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant against azithromycin weren't
established.

The clinical relevance of azithromycin in vitro susceptibility test
most current listings for other mycobacterial species, including Mycobacterium tuberculosis,
using any susceptibility testing method is not determined.

Clinical tests In Patients With Advanced Hiv Infection To the Prevention And Treatment Of Disease As a result of Disseminated Mycobacteriumavium Complex (Mac)

(See INDICATIONS):

Protection against Disseminated MAC Disease

Two randomized, double blind many studies were performed in patients with CD4 counts < 100 cells/µL. The first study (155) compared azithromycin (1200 mg once weekly) to placebo and enrolled 182 patients with a mean CD4 count of 35 cells/µL. The second 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/µL. The primary endpoint in these studies 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 trial 155, 85 patients randomized to receive azithromycin and 89 patients randomized to obtain placebo met study entrance criteria. Cumulative incidences at 6, 12 and Eighteen months on the possible outcomes will be 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 inside one full year cumulative incidence rates of disseminated MAC disease (placebo-azithromycin) is 10. 9%. This difference is statistically significant (p=0. 037) which has a 95% confidence interval because of this difference of (0. 8%, 20. 9%). The comparable quantity of patients experiencing adverse events and the fewer volume of patients lost to follow-up on azithromycin ought to be taken into account when interpreting the necessity of this difference.

In trial 174, 223 patients randomized to get rifabutin, 223 patients randomized to obtain azithromycin, and 218 patients randomized to get both rifabutin and azithromycin met study entrance criteria. Cumulative incidences at 6, 12 and 1 . 5 years with 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 competitive with rifabutin monotherapy. The gap (rifabutin-azithromycin) inside 1 year rates (7. 6%) is statistically significant (p=0. 022) with the adjusted 95% confidence interval (0. 9%, 14. 3%). Additionally, azithromycin/rifabutin combination remedies are better than rifabutin alone. The main 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 with the idea to azithromycin, rifabutin or perhaps the
combination. The distribution of MIC values for azithromycin from susceptibility
testing of the breakthrough isolates was similar between study arms. Because the
efficacy of azithromycin inside management of disseminated MAC has not been established,
the clinical relevance of those in vitro MICs as a possible indicator of susceptibility
or resistance will not be known.

Clinically Significant Disseminated MAC Disease

In association with the decreased incidence of bacteremia, patients within the groups randomized to either azithromycin alone or azithromycin along with rifabutin showed reductions within the signs 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 happened in 8. 2% of subjects treated with azithromycin and a couple. 3% of the given placebo (p=0. 121). In Study 174, more subjects discontinued through the mix 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 had to have multiple concomitant medications and experienced a range of intercurrent illnesses, that it was often difficult to attribute adverse events to study medication. Overall, the of uncomfortable side effects seen around the weekly dosage regimen of azithromycin for approximately one year in patients with advanced HIV disease was similar to that previously reported for shorter course therapies.

INCIDENCE Of a single Or even more TREATMENT RELATED* ADVERSE EVENTS**
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 Length of Therapy (days)
303
402
315
296. 1
344. 4
Discontinuation of Therapy
buy lexapro online no prescription. 82. 3
. 9 8. 2
13. 5
15. 9
22. 7
Autonomic Nerves
Mouth Dry Nerves inside the body
0
0
0
3. 0
2. 7
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 Flatulence
1. 1 4. 4
9 9
4. 7 10. 7
1. 7 5. 1
1. 8 5. 8
Nausea
11
32. 6
27. 0
16. 5
28. 1
Vomiting General
1. 1
6. 7
9. 0
3. 8
5. 8
Fever
1. 1
0
2. 1
4. 2
4. 9
Fatigue Malaise
0 0
2. 2 1. 1
3. 9 0. 4
2. 1 0
3. 12. 2
Musculoskeletal
Arthralgia Psychiatric
0
0
3. 0
4. 2
7. 1
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 color
0
0
0
2. 1
2. 2
Special Senses
Tinnitus
4. 4
3. 4
0. 9
1. 3
0. 9
Hearing Decreased Uveitis
2. 2 0
1. 1 0
0. 9 0. 4
0. 41. 3
01. 8
Taste Perversion
0
0
1. 3
2. 5
1. 3
* Includes those events considered possibly
or probably linked to study drug

** > 2% adverse event rates for just about any group (except uveitis).

Side effects related to the gastrointestinal tract were seen more frequently in patients receiving azithromycin when compared to those receiving placebo or rifabutin. In Study 174, 86% of diarrheal episodes were mild to moderate naturally with discontinuation of therapy this is why occurring within 9/233 (3. 8%) of patients.

Changes in Laboratory Values

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

Prophylaxis Against Disseminated MAC Abnormal Laboratory
Values*

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%
SCOT > 5 x ULNa
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%
a=Upper Limit of Normal

*excludes subjects not in the relevant normal range at baseline

Therapy for Disseminated MAC Disease

One randomized, double blind medical trial (Study 189) was performed in patients with disseminated MAC. Within this trial, 246 HIV infected patients with disseminated MAC received either azithromycin 250 mg qd (N=65), azithromycin 600 mg qd (N=91) or clarithromycin 500 mg bid (N=90), each administered with ethambutol 15 mg/kg qd, for 24 weeks. Patients were cultured and clinically assessed every 3 weeks through week 12 and monthly thereafter through week 24. After week 24, patients were switched to your open label therapy with the discretion from the investigator and followed every 3 months over the last follow-up visit in the trial. Patients were followed from the baseline visit for any duration of nearly 3. Several years (median: 9 months). MAC isolates recovered during study treatment or post-treatment were obtained anytime you can.

The primary endpoint was sterilization by week 24. Sterilization scaled like data from your central laboratory, and was thought as two consecutive observed negative blood cultures for MAC, separate from missing culture data relating to the two negative observations. Analyses were performed on all randomized patients who a positive baseline culture for MAC.

The azithromycin 250 mg arm was discontinued after an interim analysis at 12 weeks showed an extremely lower clearance of bacteremia in comparison with clarithromycin 500 mg bid.

Efficacy outcomes for the azithromycin 600 mg qd and clarithromycin 500
mg bid treatment regimens are described inside the following table:

Reply to therapy of patients taking ethambutol
and only azithromycin 600 mg qd or clarithromycin 500 mg bid
Azithromycin 600 mg qd
Clarithromycin 500 mg bid
**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]
* Primary endpoint

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

The primary endpoint, rate of sterilization of blood cultures (two consecutive
negative cultures) at 24 weeks, was lacking in the azithromycin 600 mg qd group
compared to the clarithromycin 500 mg bid group.

Sterilization by Baseline Colony Count

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

Azithromycin 600 mg (N=68)
Clarithromycin 500 mg bid(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%)
1 1-100 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, during breakthrough on therapy or during post-therapy follow-up. The T100 radiometric broth method was helpful to determine azithromycin and clarithromycin MIC values. Azithromycin MIC values ranged from 256 µg/mL and clarithromycin MICs ranged from 32 µg/mL. The average person MAC susceptibility results indicated that azithromycin MIC values might be 4 to 32 fold higher than clarithromycin MIC values.

During study treatment and post-treatment follow-up for as much as 3. Many years (median: 9 months) in study 189, a complete of 6/68 (9%) and 6/57 (11%) of the patients randomized to azithromycin 600 mg daily and clarithromycin 500 mg bid, respectively, developed MAC blood culture isolates that have a clear improvement in MIC values. All twelve MAC isolates had azithromycin MIC's ≥ 256 µg/mL and clarithromycin MIC's > 32 µg/mL. Elevated MIC values suggest progression of drug resistance. However, at this time, specific breakpoints for separating susceptible and resistant MAC isolates were not established for either macrolide.

Animal Toxicology

Phospholipidosis (intracellular phospholipid binding) is affecting some tissues of mice, rats, and dogs given multiple doses of azithromycin. Many experts have demonstrated in various organ systems (e. g. , eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and pancreas) in dogs administered doses which, dependant on pharmacokinetics, are the small sum of 2 times over the recommended adult human dose plus rats at doses just like the recommended adult human dose. This effect has been reversible after cessation of azithromycin treatment. The significance of these findings for humans is unknown.

REFERENCES:

1. National Committee for Clinical Laboratory Standards. Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically-Third
Edition. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova,
PA, December 1993.

2. National Committee for Clinical Laboratory Standards. Performance Standards
for Antimicrobial Disk Susceptibility Tests-Fifth Edition. Approved Standard
NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, December 1993.

3. Dunne MW, Foulds G, Retsema JA. Rationale with the utilization of azithromycin as
Mycobacterium avium chemoprophylaxis. American JMedicine 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. Resolution 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: 1/31/2011
This monograph has become modified to add in the generic and brand in most cases.

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