CLINICAL PHARMACOLOGY
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.
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FIGURE 1
|
|
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
(g) |
Route |
Hours
Post-injection |
Number
of
Patients |
Mean
Concentration
(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. |
| 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 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.
Microbiology
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
(mcg/mL) |
Disk Diffusion Zone Diameters
(mm) |
(S)
Susceptible |
(I)
Intermediate |
(R)
Resistant |
(S)
Susceptible |
(I)
Intermediate |
(R)
Resistant |
|
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 |
Haemophilus
influenzae
a
|
≤2 |
- |
- |
≥26 |
- |
- |
Pseudomonas
aeruginosa
|
≤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
Concentrations
(mcg/mL) |
Disk Diffusion Zone
Diameters
(mm) |
|
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 |
|
