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Azactam (Aztreonam) - Description and Clinical Pharmacology


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.


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 (eg, 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:

C<sub>13</sub>H<sub>17</sub>N<sub>5</sub>O<sub>8</sub>S<sub>2</sub>       MW

C13H17N5O8S2       MW 435.44

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.


Single 30-minute intravenous infusions of 500 mg, 1 g, and 2 g doses of AZACTAM in healthy subjects produced aztreonam peak serum levels of 54 mcg/mL, 90 mcg/mL, and 204 mcg/mL, respectively, immediately after administration; at 8 hours, serum levels were 1 mcg/mL, 3 mcg/mL, and 6 mcg/mL, respectively (Figure 1). Single 3-minute intravenous injections of the same doses resulted in serum levels of 58 mcg/mL, 125 mcg/mL, and 242 mcg/mL at 5 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 1 hour. After identical single intravenous or intramuscular doses of AZACTAM, the serum concentrations of aztreonam are comparable at 1 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 8 hours (for Enterobacter sp., the 8-hour serum levels exceed the MIC for 80% of strains). For Pseudomonas aeruginosa, a single 2 g intravenous dose produces serum levels that exceed the MIC90 for approximately 4 to 6 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 (1.5-2.0) 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 mcg/mL, 3500 mcg/mL, and 6600 mcg/mL within the first 2 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 mcg/mL. After intramuscular injection of single 500 mg and 1 g doses of AZACTAM, urinary levels were approximately 500 mcg/mL and 1200 mcg/mL, respectively, within the first 2 hours, declining to 180 mcg/mL and 470 mcg/mL in the 6- to 8-hour specimens. In healthy subjects, aztreonam is excreted in the urine about equally by active tubular secretion and glomerular filtration. Approximately 60% to 70% of an intravenous or intramuscular dose was recovered in the urine by 8 hours. Urinary excretion of a single parenteral dose was essentially complete by 12 hours after injection. About 12% 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 8 hours for 7 days to healthy subjects produced no apparent accumulation of aztreonam or modification of its disposition characteristics; serum protein binding averaged 56% and was independent of dose. An average of about 6% 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 0- to 8-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:

Table 1: Extravascular Concentrations of Aztreonam After a Single Parenteral Dosea
Fluid or Tissue Dose
Route Hours
(mcg/mL or mcg/g)
a Tissue penetration is regarded as essential to therapeutic efficacy, but specific tissue levels have not been correlated with specific therapeutic effects.
   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
   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 mcg/mL; in human milk at 2 hours after a single 1 g intravenous dose (6 patients), 0.2 mcg/mL, and at 6 hours after a single 1 g intramuscular dose (6 patients), 0.3 mcg/mL; in amniotic fluid at 6 to 8 hours after a single 1 g intravenous dose (5 patients), 2 mcg/mL. The concentration of aztreonam in peritoneal fluid obtained 1 to 6 hours after multiple 2 g intravenous doses ranged between 12 mcg/mL and 90 mcg/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 aztreonam 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.


Mechanism of Action

Aztreonam is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Aztreonam has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria.

Mechanism of Resistance

Resistance to aztreonam is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability.

Interaction with Other Antimicrobials

Aztreonam and aminoglycosides have been shown to be synergistic in vitro against most strains of P. aeruginosa, many strains of Enterobacteriaceae, and other Gram-negative aerobic bacilli.

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 5 section.

Aerobic Gram-negative microorganisms:

  •   Citrobacter species
  •   Enterobacter species
  •   Escherichia coli
  •   Haemophilus influenzae (including ampicillin-resistant and other penicillinase-producing strains)
  •   Klebsiella oxytoca
  •   Klebsiella pneumoniae
  •   Proteus mirabilis
  •   Pseudomonas aeruginosa
  •   Serratia species

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for aztreonam. However, the efficacy of aztreonam in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Aerobic Gram-negative microorganisms:

  •   Aeromonas hydrophila
  •   Morganella morganii
  •   Neisseria gonorrhoeae (including penicillinase-producing strains)
  •   Pasteurella multocida
  •   Proteus vulgaris
  •   Providencia stuartii
  •   Providencia rettgeri
  •   Yersinia enterocolitica

Aztreonam and aminoglycosides have been shown to be synergistic in vitro against most strains of P. aeruginosa, many strains of Enterobacteriaceae, and other Gram-negative aerobic bacilli.

Alterations of the anaerobic intestinal flora by broad-spectrum antibiotics may decrease colonization resistance, thus permitting overgrowth of potential pathogens, eg, Candida and Clostridium species. Aztreonam has little effect on the anaerobic intestinal microflora in in vitro studies. Clostridium difficile and its cytotoxin were not found in animal models following administration of aztreonam. (See ADVERSE REACTIONS: Gastrointestinal .)

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution Techniques

Quantitative methods are used to determine antimicrobial MICs.1-3 These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method6 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of aztreonam powder. The MIC values should be interpreted according to the criteria in Table 2.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.6,7 This procedure uses paper disks impregnated with 30 mcg aztreonam to test the susceptibility of microorganisms to aztreonam. The disk diffusion interpretive criteria are provided in Table 2.

Table 2: Susceptibility Test Interpretive Criteria for Aztreonam
Pathogen Minimum Inhibitory Concentrations
Disk Diffusion Zone Diameters
a The current absence of data on resistant isolates precludes defining any category other than “Susceptible.” If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for additional testing.
Enterobacteriaceae ≤4 8 ≥16 ≥21 18-20 ≤17
≤2 - - ≥26 - -
≤8 16 ≥32 ≥22 16-21 ≤15

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test.6-8 Standard aztreonam powder should provide the following range of MIC values noted in Table 3. For the diffusion technique using the 30 mcg disk, the criteria in Table 3 should be achieved.

Table 3: Acceptable Quality Control Ranges for Aztreonam
QC Strain Minimum Inhibitory
Disk Diffusion Zone
Escherichia coli ATCC 25922 0.06-0.25 28-36
Haemophilus influenzae ATCC 49247 0.12-5 30-38
Pseudomonas aeruginosa ATCC 27853 2-8 23-29

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