azactam (AZTREONAM) injection, powder, for solution
[Bristol-Myers Squibb Company]
To reduce the development of drug-resistant bacteria and maintain the effectiveness of AZACTAM® and other antibacterial drugs, AZACTAM should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
DESCRIPTION
AZACTAM® (aztreonam for injection, USP) contains the active ingredient aztreonam, a monobactam. It was originally isolated from Chromobacterium violaceum. It is a synthetic bactericidal antibiotic.
The monobactams, having a unique monocyclic beta-lactam nucleus, are structurally different from other beta-lactam antibiotics (e.g., penicillins, cephalosporins, cephamycins). The sulfonic acid substituent in the 1-position of the ring activates the beta-lactam moiety; an aminothiazolyl oxime side chain in the 3-position and a methyl group in the 4-position confer the specific antibacterial spectrum and beta-lactamase stability.
Aztreonam is designated chemically as (Z)-2-[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2-methylpropionic acid. Structural formula:
AZACTAM is a sterile, nonpyrogenic, sodium-free, white powder containing approximately 780 mg arginine per gram of aztreonam. Following constitution, the product is for intramuscular or intravenous use. Aqueous solutions of the product have a pH in the range of 4.5 to 7.5.
CLINICAL PHARMACOLOGY
Single 30-minute intravenous infusions of 500-mg, 1-g and 2-g doses of AZACTAM (aztreonam for injection, USP) in healthy subjects produced aztreonam peak serum levels of 54, 90 and 204 µg/mL, respectively, immediately after administration; at eight hours, serum levels were 1, 3 and 6 µg/mL, respectively (Figure 1). Single 3-minute intravenous injections of the same doses resulted in serum levels of 58, 125 and 242 µg/mL at five minutes following completion of injection.
Serum concentrations of aztreonam in healthy subjects following completion of single intramuscular injections of 500-mg and 1-g doses are depicted in Figure 1; maximum serum concentrations occur at about one hour. After identical single intravenous or intramuscular doses of AZACTAM, the serum concentrations of aztreonam are comparable at one hour (1.5 hours from start of intravenous infusion) with similar slopes of serum concentrations thereafter.
The serum levels of aztreonam following single 500-mg or 1-g (intramuscular or intravenous) or 2-g (intravenous) doses of AZACTAM exceed the MIC90 for Neisseria sp., Haemophilus influenzae and most genera of the Enterobacteriaceae for eight hours (for Enterobacter sp., the eight-hour serum levels exceed the MIC for 80 percent of strains). For Pseudomonas aeruginosa, a single 2-g intravenous dose produces serum levels that exceed the MIC90 for approximately four to six hours. All of the above doses of AZACTAM result in average urine levels of aztreonam that exceed the MIC90 for the same pathogens for up to 12 hours.
When aztreonam pharmacokinetics were assessed for adult and pediatric patients, they were found to be comparable (down to 9-months old). The serum half-life of aztreonam averaged 1.7 hours (1.5 to 2.0) in subjects with normal renal function, independent of the dose and route of administration. In healthy subjects, based on a 70 kg person, the serum clearance was 91 mL/min and renal clearance was 56 mL/min; the apparent mean volume of distribution at steady-state averaged 12.6 liters, approximately equivalent to extracellular fluid volume.
In elderly patients, the mean serum half-life of aztreonam increased and the renal clearance decreased, consistent with the age-related decrease in creatinine clearance.1-4 The dosage of AZACTAM should be adjusted accordingly (see DOSAGE AND ADMINISTRATION: Renal Impairment in Adult Patients).
In patients with impaired renal function, the serum half-life of aztreonam is prolonged. (See DOSAGE AND ADMINISTRATION: Renal Impairment in Adult Patients.) The serum half-life of aztreonam is only slightly prolonged in patients with hepatic impairment since the liver is a minor pathway of excretion.
Average urine concentrations of aztreonam were approximately 1100, 3500 and 6600 µg/mL within the first two hours following single 500-mg, 1-g and 2-g intravenous doses of AZACTAM (30-minute infusions), respectively. The range of average concentrations for aztreonam in the 8- to 12- hour urine specimens in these studies was 25 to 120 µg/mL. After intramuscular injection of single 500 mg and 1 g doses of AZACTAM (aztreonam for injection, USP), urinary levels were approximately 500 and 1200 µg/mL, respectively, within the first two hours, declining to 180 and 470 µg/mL in the six to eight hour specimens. In healthy subjects, aztreonam is excreted in the urine about equally by active tubular secretion and glomerular filtration. Approximately 60 to 70 percent of an intravenous or intramuscular dose was recovered in the urine by eight hours. Urinary excretion of a single parenteral dose was essentially complete by 12 hours after injection. About 12 percent of a single intravenous radiolabeled dose was recovered in the feces. Unchanged aztreonam and the inactive beta-lactam ring hydrolysis product of aztreonam were present in feces and urine.
Intravenous or intramuscular administration of a single 500-mg or 1-g dose of AZACTAM every eight hours for seven days to healthy subjects produced no apparent accumulation of aztreonam or modification of its disposition characteristics; serum protein binding averaged 56 percent and was independent of dose. An average of about 6 percent of a 1-g intramuscular dose was excreted as a microbiologically inactive open beta-lactam ring hydrolysis product (serum half-life approximately 26 hours) of aztreonam in the zero to eight hour urine collection on the last day of multiple dosing.
Renal function was monitored in healthy subjects given aztreonam; standard tests (serum creatinine, creatinine clearance, BUN, urinalysis and total urinary protein excretion) as well as special tests (excretion of N-acetyl-β-glucosaminidase, alanine aminopeptidase and β2-microglobulin) were used. No abnormal results were obtained.
Aztreonam achieves measurable concentrations in the following body fluids and tissues:
EXTRAVASCULAR CONCENTRATIONS OF AZTREONAM AFTER A SINGLE PARENTERAL DOSE 1
Fluid or Tissue |
Dose
(g) |
Route |
Hours
Post-injection |
Number
of
Patients |
Mean
Concentration
(µg/mL or µg/g) |
|
1Tissue penetration is regarded as essential to therapeutic efficacy, but specific tissue levels have not been correlated with specific therapeutic effects. |
|
Fluids |
|
|
|
|
|
|
bile |
1 |
IV |
2 |
10 |
39 |
|
blister fluid |
1 |
IV |
1 |
6 |
20 |
|
bronchial secretion |
2 |
IV |
4 |
7 |
5 |
cerebrospinal fluid
(inflamed meninges) |
2 |
IV |
0.9-4.3 |
16 |
3 |
|
pericardial fluid |
2 |
IV |
1 |
6 |
33 |
|
pleural fluid |
2 |
IV |
1.1-3.0 |
3 |
51 |
|
synovial fluid |
2 |
IV |
0.8-1.9 |
11 |
83 |
|
Tissues |
|
|
|
|
|
|
atrial appendage |
2 |
IV |
0.9-1.6 |
12 |
22 |
|
endometrium |
2 |
IV |
0.7-1.9 |
4 |
9 |
|
fallopian tube |
2 |
IV |
0.7-1.9 |
8 |
12 |
|
fat |
2 |
IV |
1.3-2.0 |
10 |
5 |
|
femur |
2 |
IV |
1.0-2.1 |
15 |
16 |
|
gallbladder |
2 |
IV |
0.8-1.3 |
4 |
23 |
|
kidney |
2 |
IV |
2.4-5.6 |
5 |
67 |
|
large intestine |
2 |
IV |
0.8-1.9 |
9 |
12 |
|
liver |
2 |
IV |
0.9-2.0 |
6 |
47 |
|
lung |
2 |
IV |
1.2-2.1 |
6 |
22 |
|
myometrium |
2 |
IV |
0.7-1.9 |
9 |
11 |
|
ovary |
2 |
IV |
0.7-1.9 |
7 |
13 |
|
prostate |
1 |
IM |
0.8-3.0 |
8 |
8 |
|
skeletal muscle |
2 |
IV |
0.3-0.7 |
6 |
16 |
|
skin |
2 |
IV |
0.0-1.0 |
8 |
25 |
|
sternum |
2 |
IV |
1 |
6 |
6 |
The concentration of aztreonam in saliva at 30 minutes after a single 1-g intravenous dose (9 patients) was 0.2 µg/mL; in human milk at two hours after a single 1-g intravenous dose (6 patients), 0.2 µg/mL, and at six hours after a single 1-g intramuscular dose (6 patients), 0.3 µg/mL; in amniotic fluid at six to eight hours after a single 1-g intravenous dose (5 patients), 2 µg/mL. The concentration of aztreonam in peritoneal fluid obtained one to six hours after multiple 2-g intravenous doses ranged between 12 and 90 µg/mL in 7 of 8 patients studied.
Aztreonam given intravenously rapidly reaches therapeutic concentrations in peritoneal dialysis fluid; conversely, aztreonam given intraperitoneally in dialysis fluid rapidly produces therapeutic serum levels.
Concomitant administration of probenecid or furosemide and AZACTAM (aztreonam for injection, USP) causes clinically insignificant increases in the serum levels of aztreonam. Single-dose intravenous pharmacokinetic studies have not shown any significant interaction between aztreonam and concomitantly administered gentamicin, nafcillin sodium, cephradine, clindamycin or metronidazole. No reports of disulfiram-like reactions with alcohol ingestion have been noted; this is not unexpected since aztreonam does not contain a methyl-tetrazole side chain.
Microbiology
Aztreonam exhibits potent and specific activity in vitro against a wide spectrum of gram-negative aerobic pathogens including Pseudomonas aeruginosa. The bactericidal action of aztreonam results from the inhibition of bacterial cell wall synthesis due to a high affinity of aztreonam for penicillin binding protein 3 (PBP3). Aztreonam, unlike the majority of beta-lactam antibiotics, does not induce beta-lactamase activity and its molecular structure confers a high degree of resistance to hydrolysis by beta-lactamases (i.e., penicillinases and cephalosporinases) produced by most gram-negative and gram-positive pathogens; it is, therefore, usually active against gram-negative aerobic microorganisms that are resistant to antibiotics hydrolyzed by beta-lactamases. It is active against many strains that are multiply-resistant to other antibiotics, such as certain cephalosporins, penicillin, and aminoglycosides. Aztreonam maintains its antimicrobial activity over a pH range of 6 to 8 in vitro, as well as in the presence of human serum and under anaerobic conditions.
Aztreonam has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
