Aztreonam

Name: Aztreonam

Adverse Effects

>10%

Inhalation

  • Cough (54%)
  • Sore throat (12%)
  • Wheezing (16%)
  • Fever (13%)

Injection

  • Pain at injection site (12%; children); (2%; adults)
  • Increase in serum transaminases (4-6%)
  • Neutropenia (3-11%, children); (<1%, adults)

1-10%

Inhalation

  • Chest discomfort (8%)
  • Abdominal pain (7%)
  • Vomiting (6%)
  • Bronchospasm (3%)
  • Skin rash (2%)

Injection

  • Rash (4%)
  • Thrombocytopenia (4%, children); (<1% adults)
  • Diarrhea (1%)
  • Nausea (1%)
  • Vomiting (1%)
  • Fever (<1%)

< 1%

Inhalation

Facial edema

Joint swelling

Tightness in chest and throat

Bronchospasm

Skin rash

Injection

Abnormal taste

Anaphylaxis

Anemia

Angioedema

Aphthous ulcer

Breast tenderness

Bronchospasm

Clostridium difficile-associated diarrhea (CDAD)

Confusion

Diplopia

Dizziness

Dsypnea

Electrocardiographic changes (transient)

Erythema multiforme

Eosinophilia

Fever

Flushing

Halitosis

Headache

Hepatitis

Hypotension

Insomnia

Jaundice

Leukocytosis

Neutropenia

Pancytopenia

Seizures

Thrombocytopenia

Tinnitus

Tongue numbness

Toxic epidermal necrolysis

Urticaria

Vaginitis

Vertigo

Weakness

Wheezing

Aztreonam Food Interactions

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of aztreonam there are no specific foods that you must exclude from your diet when receiving Cayston.

 

Other Requirements

Injectable:

  • Avoid excessive heat.

Inhalation:

  • Each aztreonam kit contains enough vials of aztreonam and ampules of saline for 28 days of treatment. There are 4 extra saline ampules in case some saline spills.
  • Always keep your aztreonam and saline together.
  • Store aztreonam and saline in the refrigerator at 36 °F to 46 °F (2 °C to 8 °C) until needed.
  • When you remove aztreonam and saline from the refrigerator, they may be stored at room temperature (less than 77 °F) for up to 28 days. Do not use any aztreonam that has been stored at room temperature for more than 28 days.
  • Keep aztreonam away from light.
  • Do not use aztreonam after the expiration date on the vial. Do not use the saline after the expiration date on the ampule.

Keep aztreonam and all medicines out of the reach of children.

Uses for Aztreonam

Bone and Joint Infections

Treatment of bone and joint infections† (including osteomyelitis or septic arthritis) caused by susceptible gram-negative bacteria, including Enterobacter, Escherichia coli, Haemophilus influenzae†, Klebsiella, Proteus mirabilis, Pseudomonas aeruginosa, or Serratia marcescens.48 166 172 173 177 178 220 267 268 282

If gram-positive bacteria known or suspected to also be involved, regimen should also include an antistaphylococcal anti-infective (e.g., penicillinase-resistant penicillin, vancomycin).177

IDSA states aztreonam is an alternative for treatment of native vertebral osteomyelitis† caused by Ps. aeruginosa if a drug of first choice (i.e., cefepime, meropenem, doripenem) cannot be used because of severe penicillin allergy and ciprofloxacin cannot be used because of quinolone-resistant strains.590

Consult current IDSA clinical practice guidelines available at for additional information on management of osteomyelitis.590

Gynecologic Infections

Treatment of gynecologic infections (including endometritis and pelvic cellulitis) caused by susceptible gram-negative bacteria, including Enterobacter (including E. cloacae), E. coli, K. pneumoniae, or P. mirabilis.1 171 173 183 192 211 253 287

Do not use alone for empiric treatment of gynecologic infections since these usually are polymicrobial and frequently are mixed aerobic-anaerobic bacterial infections.171 173 183 211 Clindamycin or metronidazole generally used concomitantly if aztreonam used for initial treatment of gynecologic infections.171 173 177 183 211 267

Intra-abdominal Infections

Treatment of intra-abdominal infections (including peritonitis) caused by susceptible gram-negative bacteria, including Citrobacter (including C. freundii), Enterobacter (including E. cloacae), E. coli, Klebsiella (including K. pneumoniae), Ps. aeruginosa, or Serratia (including S. marcescens).1 173 177 213 214 253 267 287

Do not use alone for empiric treatment of intra-abdominal infections since these usually are polymicrobial and frequently are mixed aerobic-anaerobic bacterial infections.173 213 214 267 Clindamycin or metronidazole generally used concomitantly if aztreonam used for initial treatment of intra-abdominal infections.173 177 213 214 228

For initial empiric treatment of high-risk or severe community-acquired, extrabiliary, complicated intra-abdominal infections in adults, IDSA states that aztreonam in conjunction with metronidazole is an alternative regimen, but an additional anti-infective active against gram-positive bacteria is recommended pending results of in vitro culture and susceptibility tests.708

Consult current IDSA clinical practice guidelines available at for additional information on management of intra-abdominal infections.708

Intraperitoneal†: Has been used for treatment of peritonitis in patients undergoing CAPD.312 313 314 315 Some clinicians suggest that intraperitoneal anti-infectives are preferred over IV anti-infectives for empiric treatment of peritonitis in CAPD patients;312 regimen should provide coverage against both gram-positive and gram-negative bacteria pending results of in vitro culture and susceptibility testing.312 Intraperitoneal vancomycin in conjunction with intraperitoneal aztreonam has been used;314 315 aztreonam recommended as an alternative for gram-negative coverage in CAPD patients allergic to cephalosporins.312

Respiratory Tract Infections

Treatment of lower respiratory tract infections (including pneumonia and bronchitis) caused by susceptible gram-negative bacteria, including Enterobacter, E. coli, H. influenzae, K. pneumoniae, Ps. aeruginosa, P. mirabilis, or S. marcescens.1 165 167 168 169 173 176 177 192 206 208 222 253 287

Also has been used for treatment of lower respiratory tract infections caused by susceptible Citrobacter†,167 168 176 206 208 264 267 Hafnia†,264 K. oxytoca†,168 Morganella†,206 208 264 P. vulgaris†,165 Providencia stuartii†,192 or Moraxella catarrhalis†.165 208 264

Do not use alone for empiric treatment of lower respiratory tract infections since these infections frequently are caused by gram-positive and/or anaerobic bacteria.1 48 164 165 176 186 202 206 208 223 235 241 253 266 268 287

Clindamycin in conjunction with aztreonam has been used for initial empiric treatment of lower respiratory tract infections (especially nosocomial infections).165 167 206 235 268

Consult current IDSA clinical practice guidelines available at for additional information on management of respiratory tract infections, including community-acquired pneumonia (CAP).512 513

Oral inhalation via nebulization: Used to improve respiratory symptoms in cystic fibrosis patients ≥7 years of age with Ps. aeruginosa in the lungs.306 307 308 309 310 Safety and efficacy not established in pediatric patients <7 years of age, in patients with FEV1 <25% or >75% of predicted, or in patients colonized with Burkholderia cepacia.306

Septicemia

Treatment of septicemia caused by susceptible gram-negative bacteria, including Enterobacter, E. coli, K. pneumoniae, Ps. aeruginosa, P. mirabilis, or S. marcescens.1 173 176 177 186 192 221 222 223 253 287

Also has been used for treatment of septicemia caused by susceptible Citrobacter†264 267 or H. influenzae†.186 192 264

Skin and Skin Structure Infections

Treatment of skin and skin structure infections (including those associated with postoperative wounds, ulcers, and burns) caused by susceptible gram-negative bacteria, including Citrobacter, Enterobacter, E. coli, K. pneumoniae, P. mirabilis, Ps. aeruginosa, or S. marcescens.1 173 177 192 222 223 253 287

Adjunct to surgery in management of abscesses, cutaneous infections, infections complicating hollow viscus perforations, or infections of serous surfaces caused by susceptible gram-negative aerobic bacteria.1 253 287

Consult current IDSA clinical practice guidelines available at for additional information on management of skin and skin structure infections.543 544

Urinary Tract Infections (UTIs)

Treatment of uncomplicated or complicated UTIs (including pyelonephritis and initial or recurrent cystitis) caused by susceptible gram-negative bacteria, including Citrobacter, E. cloacae, E. coli, K. pneumoniae, K. oxytoca, P. mirabilis, Ps. aeruginosa, or S. marcescens.1 90 160 162 170 175 176 177 190 192 218 219 223 253 287

Also has been used for treatment of UTIs caused by susceptible E. aerogenes†,176 218 Morganella morganii†,176 218 264 267 P. vulgaris†,218 or Providencia†.177 218 264

Has been effective for treatment of cystitis or pyelonephritis caused by gram-negative aerobic bacteria resistant to aminopenicillins, first or second generation cephalosporins, and/or aminoglycosides.170 218 264 Although aztreonam generally is associated with less toxicity than aminoglycosides, colonization or superinfection with gram-positive bacteria (especially Enterococcus faecalis) has been reported more frequently with aztreonam than with aminoglycosides.46 90 160 164 175 188

Perioperative Prophylaxis

Perioperative prophylaxis† in patients undergoing certain surgical procedures in which aerobic gram-negative bacteria are common pathogens;360 374 used in conjunction with other anti-infectives.360 374

Regimen of vancomycin (or clindamycin) in conjunction with aztreonam recommended as an alternative for perioperative prophylaxis in patients undergoing gastroduodenal or biliary tract surgery, hysterectomy (vaginal or abdominal), or certain organ transplant procedures (liver, pancreas, pancreas-kidney).374 Regimen of clindamycin and aztreonam also considered an alternative in patients undergoing appendectomy, colorectal or small intestine surgery, or urologic surgery involving an implanted prosthesis.374

Some clinicians recommend concomitant use of an anti-infective active against enteric gram-negative bacilli (e.g., aztreonam, aminoglycoside, fluoroquinolone) when vancomycin used for perioperative prophylaxis in patients undergoing neurosurgery or cardiac, orthopedic, or vascular surgery.360

Empiric Therapy in Febrile Neutropenic Patients

Has been used in conjunction with vancomycin (with or without amikacin) for empiric anti-infective therapy in febrile granulocytopenic adults†.180 216 Because gram-positive bacteria (especially Staphylococcus epidermidis) reported with increasing frequency in febrile granulocytopenic patients and because aztreonam is inactive against these organisms, an anti-infective active against staphylococci (e.g., vancomycin) also should be used if aztreonam is used for empiric therapy in these patients.215 268 457 A regimen of aztreonam and vancomycin is considered an alternative empiric regimen in patients with immediate-type penicillin hypersensitivity.457

Consult published protocols for treatment of infections in febrile neutropenic patients for specific recommendations regarding selection of initial empiric regimen, when to change the initial regimen, possible subsequent regimens, and duration of therapy in these patients.457

Interactions for Aztreonam

Drug interactions based on parenteral aztreonam.1 253 Formal interaction studies not conducted to date using aztreonam by oral inhalation via nebulization.306

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Aminoglycosides

No clinically important effects on aztreonam pharmacokinetics1 253

In vitro evidence of additive or synergistic antibacterial effects against Ps. aeruginosa1 38 48 57 78 88 107 111 112 128 131 140 and some strains of Ps. cepacia48 107 131 Ps. fluorescens,131 or Ps. maltophilia131

In vitro evidence of synergistic antibacterial effects against Enterobacteriaceae (e.g., Enterobacter, E. coli, Klebsiella, Serratia)1 57 78 88 140

In vitro synergism reported occasionally against Acinetobacter, but usually only additive or indifferent131 264

Indifference reported against gram-positive bacteria (e.g., S. aureus, S. epidermidis, E. faecalis)88 92 131

Monitor renal function, especially if high aminoglycoside dosage used or if therapy is prolonged;1 253 risk of aminoglycoside-associated nephrotoxicity and ototoxicity1 253

Chloramphenicol

In vitro studies using K. pneumoniae indicate chloramphenicol can antagonize bactericidal activity of aztreonam139

If used concomitantly, some clinicians suggest administering chloramphenicol a few hours after aztreonam;139 necessity of this precaution not established139

Clavulanic acid

In vitro evidence of synergistic effects against some β-lactamase-producing Enterobacter, Klebsiella, or B. fragilis;48 88 antagonism also may occur127 276

Concomitant use does not alter in vitro susceptibility of S. aureus to aztreonam since resistance to the drug in these organisms is intrinsic234

Clindamycin

Possible increased total urinary excretion of aztreonam, but other pharmacokinetic parameters not affected154

In vitro evidence of synergistic effects against some strains of E. coli, Klebsiella, or Enterobacter, indifferent or additive effects reported more frequently77

Indifferent or slightly additive effects reported against anaerobic bacteria38 264

Not considered clinically important1 154 253

Furosemide

Possible increased serum aztreonam concentrations1

Not considered clinically important1

β-lactam antibiotics

Nafcillin: No clinically important pharmacokinetic interactions1 253

In vitro evidence of additive or synergistic antibacterial effects with some β-lactams (piperacillin, cefotaxime) against some strains of Ps. aeruginosa;78 antagonism with imipenem against Ps. aeruginosa92

In vitro evidence of indifferent or only slightly additive effects with some β-lactams (ampicillin, piperacillin, cefotaxime) against Enterobacteriaceae, including Enterobacter, E. coli, S. marcescens, or Klebsiella77 78 92

In vitro evidence of synergism with cefoxitin against some strains of Enterobacter, E. coli, Klebsiella, S. marcescens, Salmonella, or Shigella;77 antagonism also reported against some Enterobacter or S. marcescens77 127

Because of potential for antagonism, do not use β-lactams that are potent inducers of β-lactamase production (e.g., cefoxitin, imipenem) concomitantly with aztreonam1 264 253

Metronidazole

Possible decreased peak serum concentrations of aztreonam;154 other pharmacokinetic parameters not affected154

In vitro evidence of indifferent or slightly additive effects against anaerobic bacteria38 264

Not considered clinically important1 154 253

Probenecid

Decreased rate of renal tubular secretion of aztreonam and increased aztreonam concentrations:1 2 34 56 253 decreased binding of aztreonam to plasma proteins1 2 34 56 253

Not sufficient to be of therapeutic benefit1 2 34 56 253

Tests for glucose

Possible false-positive reactions in urine glucose tests using Clinitest, Benedict’s solution, or Fehling’s solution240

Use glucose tests based on enzymatic glucose oxidase reactions (e.g., Clinistix, Tes-Tape)240

Aztreonam Pharmacokinetics

Absorption

Bioavailability

IM: Rapidly and completely absorbed following IM administration;2 6 7 29 46 47 48 56 256 peak serum concentrations generally attained within 1 hour after an IM dose.1 2 6 7 29 46 Peak serum concentrations attained with IM dose are slightly lower than those attained with equivalent IV dose, but serum aztreonam concentrations ≥1 hour after dosing are similar.1 2 264

Oral inhalation via nebulization: Variable concentrations enter systemic circulation;306 307 308 accumulation does not occur following multiple doses.306 307 308

Special Populations

IV: Pharmacokinetics in pediatric patients ≥9 months of age similar to those in adults.1

Distribution

Extent

IV or IM: Widely distributed into body tissues and fluids.21 46 48 264 Distributed into skeletal muscle,1 21 25 264 266 adipose tissue,1 21 264 266 skin,1 21 264 bone,1 20 25 264 gallbladder,1 21 264 liver,1 21 264 lungs,1 25 208 264 kidneys,1 2 22 264 266 atrial appendage,1 25 264 intestines,1 21 264 prostatic tissue,1 24 48 56 264 myometrium,264 266 endometrium,1 25 264 266 fallopian tubes,1 264 266 ovaries,1 264 and cervical and vaginal tissue.266 Also distributed into saliva,1 2 56 sputum,48 266 bronchial secretions,1 48 208 226 264 aqueous humor,2 6 56 and bile,1 2 7 21 31 48 56 264 and into pericardial,1 25 264 pleural,1 25 208 264 peritoneal,1 2 48 56 212 synovial,1 20 264 and blister fluids.1 2 23 46 48 56 264

IV: Distributed into CSF in adults and pediatric patients;1 2 15 17 18 19 46 48 56 223 264 CSF concentrations generally higher in patients with inflamed meninges than in those with uninflamed meninges.2 17 18 46 48 56

Oral inhalation via nebulization: Sputum concentrations exhibit considerable interindividual variation;306 307 308 accumulation does not occur following multiple doses.306 307 308

Crosses the placenta and is distributed into amniotic fluid.1 28 46 48 56

Distributed into milk in low concentrations.1 27 46 48 56 264

Plasma Protein Binding

46–60% bound to serum proteins in healthy adults1 2 6 10 14 33 34 48 56 234 264 at serum concentrations of 1–100 mcg/mL.6 10 234

Adults with impaired renal function and decreased serum albumin concentrations: 22–49% bound to serum proteins.13 33 46 48

Elimination

Metabolism

Partially metabolized to several microbiologically inactive metabolites;2 6 7 17 33 46 48 56 264 no active metabolites have been found in serum or urine.2 6 7 17 29 48 56

Elimination Route

Eliminated principally in urine as unchanged drug1 2 4 6 7 10 23 29 34 46 48 56 212 via both glomerular filtration and tubular secretion.1 2 6 23 33 34 46 48 56 212 Partially excreted in feces,1 2 7 46 48 56 152 264 presumably via biliary elimination.2 7 23 46 48 56 264

IM or IV: Approximately 58–74% of a dose excreted in urine unchanged,1 2 3 4 6 7 14 23 33 46 48 56 264 1–7% excreted as SQ 26,992 (an inactive metabolite),1 2 6 7 14 23 33 48 56 264 and 3–4% excreted as unidentified inactive metabolites.2 48 Urinary excretion of unchanged drug essentially complete 8–12 hours after single dose,1 4 6 7 10 14 29 34 but SQ 26,992 excreted for up to 48 hours after the dose.7 10 14

IV: Approximately 1% of single dose excreted in feces unchanged,2 7 48 56 3% as SQ 26,992,2 7 and 7.5–10.8% as unidentified inactive metabolites.2 7

Oral inhalation via nebulization: Approximately 10% of total dose excreted unchanged in urine;306 glomerular filtration and tubular secretion equally involved.306

Removed by hemodialysis.2 30 36 46 47 177 203 256 Removed to a lesser extent by peritoneal dialysis.1 36 47 227

Half-life

Adults with normal renal and hepatic function: Distribution half-life averages 0.2–0.7 hours2 4 6 7 9 10 14 29 33 46 48 56 and elimination half-life averages 1.3–2.2 hours.2 4 6 7 9 10 14 23 29 33 34 46 47 48 56

Children 2 months to 12 years of age: Elimination half-life averages 1.7 hours.15

Neonates: Half-life is longer than in older children and adults and is inversely related to age and birthweight.15 In neonates <7 days of age, elimination half-life averages 5.5–9.9 hours in those weighing <2.5 kg5 15 and 2.6 hours in those weighing >2.5 kg.15 In neonates 1 week to 1 month of age, elimination half-life averages 2.4 hours.15

Oral inhalation via nebulization in adults with cystic fibrosis: Plasma elimination half-life of systemically absorbed drug is approximately 2.1 hours.306

Special Populations

Geriatric adults: Elimination half-life is slightly longer than in younger adults1 14 90 266 and ranges from 1.7–4.3 hours in adults 64–82 years of age with renal function normal for their age.14 90 266

Cystic fibrosis patients: May eliminate aztreonam at a faster rate than healthy individuals.46 48 177 269 270 Serum half-life averaged 1–1.3 hours in several patients with cystic fibrosis.177 269 270

Patients with hepatic impairment: Half-life is only slightly prolonged since the liver is a minor elimination pathway for the drug.1 Elimination half-life in patients with cirrhosis but with normal renal function averages 2.2 hours in those with primary biliary cirrhosis and 3.2 hours in those with alcoholic cirrhosis.32

Patients with renal impairment: Serum concentrations of aztreonam are higher and serum half-life prolonged.1 2 30 33 46 47 48 56 203 212 264 In adults with renal impairment, elimination half-life averages 3.4–3.6, 5.3–5.9, 7.8–7.9, or 8.4–8.7 hours in adults with Clcr of 30–80, 10–29, 3–9, or <2 mL/minute, respectively.30

Advice to Patients

  • Advise patients that antibacterials (including aztreonam) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1 253 287

  • Importance of completing full course of therapy, even if feeling better after a few days.1 253 287

  • Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with aztreonam or other antibacterials in the future.1 253 287

  • Importance of discontinuing therapy and informing clinician if an allergic reaction occurs.1 253 287

  • Advise patients that diarrhea is a common problem caused by systemic anti-infectives and usually ends when the drug is discontinued.1 253 287 Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as ≥2 months after the last dose.1 253 287

  • Oral inhalation via nebulization: Advise patients to reconstitute the powder for inhalation solution using only the diluent provided by the manufacturer and to administer reconstituted solution only with the Altera nebulizer system.306

  • Oral inhalation via nebulization: Advise patients to complete the full 28-day oral inhalation regimen, even if feeling better;306 if a dose is missed, advise patient to take all 3 daily doses as long as the doses are at least 4 hours apart.306

  • Oral inhalation via nebulization: Advise patients to inform their clinician if they have new or worsening symptoms and to immediately contact a clinician if possible allergic reaction occurs.306

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.1 253 287 306

  • Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.1 253 287 306

  • Importance of advising patients of other important precautionary information.1 253 287 306 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Aztreonam

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral Inhalation

Kit

Aztreonam 75 mg powder for inhalation solution for nebulization

0.17% sodium chloride diluent

Cayston

Gilead

Parenteral

For injection

500 mg*

Aztreonam for Injection

1 g*

Azactam

Squibb

Aztreonam for Injection

2 g*

Azactam

Squibb

Aztreonam for Injection

Aztreonam in Dextrose

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection (frozen), for IV infusion

20 mg/mL (1 g) in 3.4% Dextrose

Azactam in Iso-osmotic Dextrose Injection (Galaxy [Baxter])

Squibb

40 mg/mL (2 g) in 1.4% Dextrose

Azactam in Iso-osmotic Dextrose Injection (Galaxy [Baxter])

Squibb

Clinical pharmacology

Single 30-minute intravenous infusions of 500 mg, 1 g and 2 g doses of Aztreonam for injection 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 Aztreonam for injection, 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 Aztreonam for injection 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 Aztreonam for injection 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) 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 Aztreonam for injection 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 1,100 mcg/mL, 3,500 mcg/mL and 6,600 mcg/mL within the first 2 hours following single 500 mg, 1 g and 2 g intravenous doses of Aztreonam for injection (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 Aztreonam for injection, urinary levels were approximately 500 mcg/mL and 1,200 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 Aztreonam for injection 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-ß-glucosaminidase, alanine aminopeptidase and ß2-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)


 
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 to 4.3
 

 
16
 

 
3
 

 
  pericardial fluid
 

 
2
 

 
IV
 

 
1
 

 
6
 

 
33
 

 
  pleural fluid
 

 
2
 

 
IV
 

 
1.1 to 3
 

 
3
 

 
51
 

 
  synovial fluid
 

 
2
 

 
IV
 

 
0.8 to 1.9
 

 
11
 

 
83
 

 
Tissues
 






 
  atrial appendage
 

 
2
 

 
IV
 

 
0.9 to 1.6
 

 
12
 

 
22
 

 
  endometrium
 

 
2
 

 
IV
 

 
0.7 to 1.9
 

 
4
 

 
9
 

 
  fallopian tube
 

 
2
 

 
IV
 

 
0.7 to 1.9
 

 
8
 

 
12
 

 
  fat
 

 
2
 

 
IV
 

 
1.3 to 2
 

 
10
 

 
5
 

 
  femur
 

 
2
 

 
IV
 

 
1 to 2.1
 

 
15
 

 
16
 

 
  gallbladder
 

 
2
 

 
IV
 

 
0.8 to 1.3
 

 
4
 

 
23
 

 
  kidney
 

 
2
 

 
IV
 

 
2.4 to 5.6
 

 
5
 

 
67
 

 
  large intestine
 

 
2
 

 
IV
 

 
0.8 to 1.9
 

 
9
 

 
12
 

 
  liver
 

 
2
 

 
IV
 

 
0.9 to 2
 

 
6
 

 
47
 

 
  lung
 

 
2
 

 
IV
 

 
1.2 to 2.1
 

 
6
 

 
22
 

 
  myometrium
 

 
2
 

 
IV
 

 
0.7 to 1.9
 

 
9
 

 
11
 

 
  ovary
 

 
2
 

 
IV
 

 
0.7 to 1.9
 

 
7
 

 
13
 

 
  prostate
 

 
1
 

 
IM
 

 
0.8 to 3
 

 
8
 

 
8
 

 
  skeletal muscle
 

 
2
 

 
IV
 

 
0.3 to 0.7
 

 
6
 

 
16
 

 
  skin
 

 
2
 

 
IV
 

 
0 to 1
 

 
8
 

 
25
 

 
  sternum
 

 
2
 

 
IV
 

 
1
 

 
6
 

 
6
 

a Tissue penetration is regarded as essential to therapeutic efficacy, but specific tissue levels have not been correlated with specific therapeutic effects.


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 USAGE5 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, e.g., 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
 

Enterobacteriaceae
 
≤ 4
 

 
8
 

 
≥ 16
 

 
≥ 21
 

 
18 to 20
 

 
≤ 17
 

Haemophilus
  influenzaea 
 
≤ 2
 

 

 

 

 

 
≥ 26
 

 

 

 

 

Pseudomonas
  aeruginosa
 
≤ 8
 

 
16
 

 
≥ 32
 

 
≥ 22
 

 
16 to 21
 

 
≤ 15
 

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.


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 to 0.25
 

 
28 to 36
 

Haemophilus influenzae ATCC 49247
 
0.12 to 5
 

 
30 to 38
 

Pseudomonas aeruginosa ATCC 27853
 
2 to 8
 

 
23 to 29
 

Contraindications

This preparation is contraindicated in patients with known hypersensitivity to Aztreonam or any other component in the formulation.

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