AZTREONAM (Generic for AZACTAM)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Powder vials for injection
Reconstitution
-For IV push, reconstitute each vial with 6 to 10 mL of Sterile Water for Injection.
-For intermittent IV infusion, reconstitute with at least 3 mL of Sterile Water for Injection per g of aztreonam. FURTHER DILUTION IS NECESSARY FOR IV INFUSION.
-Shake immediately and vigorously.
-Storage: Use within 48 hours if kept at room temperature (15 to 30 degrees C or 59 to 98 degrees F) or within 7 days if kept under refrigeration (2 to 8 degrees C or 38 to 48 degrees F).

Dilution for intermittent IV infusion
-Further dilute the appropriate dose in a compatible IV solution.
-If using a volume control administration set, the final dilution of aztreonam should not exceed a concentration of 20 mg/mL.
-Shake immediately and vigorously.
-Storage: For solutions at concentrations not exceeding 20 mg/mL (2% w/v) and for solutions at concentrations exceeding 20 mg/mL (2% w/v) using Sterile Water for Injection or 0.9% Sodium Chloride Injection, use within 48 hours if kept at room temperature (15 to 30 degrees C or 59 to 98 degrees F) or within 7 days if kept under refrigeration (2 to 8 degrees C or 38 to 48 degrees F). For other solutions at concentrations exceeding 20 mg/mL (2% w/v), use promptly after preparation.

Pre-mixed Galaxy IV solution
Preparation
-Thaw frozen containers at room temperature (25 degrees C or 77 degrees F) or under refrigeration (2 to 8 degrees C or 36 to 46 degrees F). Do not force thaw by immersion in water baths or by microwave irradiation. Check for leaks by squeezing bag firmly. Do not add supplementary medication.
-Contents of the solution may precipitate in the frozen state and should dissolve with little or no agitation once the solution has reached room temperature.
-Storage: The thawed solution is stable for 48 hours at room temperature or 14 days under refrigeration.

Intermittent IV injection

-Slowly inject directly into a vein or the tubing of a suitable administration set over 3 to 5 minutes.

Intermittent IV infusion
-Infuse appropriate dose IV over 20 to 60 minutes.
-For neonates, an infusion time of 15 minutes has been recommended.
-For premixed-bags, do not use plastic containers in series connections as this could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

Intramuscular Administration
Reconstitution
-Reconstitute vials with at least 3 mL of an appropriate diluent per g of aztreonam.
-Shake immediately and vigorously.
-Storage: For solutions at concentrations not exceeding 20 mg/mL (2% w/v) and for solutions at concentrations exceeding 20 mg/mL (2% w/v) using Sterile Water for Injection or 0.9% Sodium Chloride Injection, use within 48 hours if kept at room temperature (15 to 30 degrees C or 59 to 98 degrees F) or within 7 days if kept under refrigeration (2 to 8 degrees C or 38 to 48 degrees F). For other solutions at concentrations exceeding 20 mg/mL (2% w/v), use promptly after preparation.

Intramuscular injection
-According to the FDA-approved product labeling, there are insufficient data regarding intramuscular administration of aztreonam in pediatric patients ; however, aztreonam has been administered IM to pediatric patients in clinical practice when acceptable IV access was not available.
-Inject deeply into a large muscle mass (e.g., anterolateral thigh). When multiple IM injections are necessary, rotate administration sites.
-In general, IM administration of antibiotics in very low birth weight premature neonates is not practical due to small muscle mass, and absorption is unreliable due to hemodynamic instability that is relatively common in this population.
-Aztreonam is well tolerated; do not admix with any local anesthetic agent.



Inhalation Administration
Oral Inhalation Administration
Reconstitution of nebulized solution
-Do not reconstitute aztreonam for inhalation until ready to administer a dose.
-Gently tap the aztreonam vial so that the powder settles to the bottom of the vial.
-Using the blue cap tab, slowly flip up the blue cap. Pull the blue cap down to a horizontal position, where the bottom of the blue cap faces up.
-Slowly pull the blue cap in a counterclockwise direction until the metal seal opens and is completely removed. Do not twist the blue cap.
-Carefully remove the rubber stopper.
-Twist the tip off of the provided 1 mL sterile diluent (0.17% Sodium Chloride) ampule and squeeze contents into the aztreonam vial.
-Gently swirl the vial until the contents have completely dissolved.

Administration of nebulized solution
-Have patient use a bronchodilator before administration of the aztreonam nebulized solution. A short-acting bronchodilator can be administered 15 minutes to 4 hours before aztreonam. Alternatively, a long-acting bronchodilator can be administered 30 minutes to 12 hours before aztreonam. For patients taking multiple inhaled therapies, the recommended order of administration is bronchodilator, mucolytic, and then aztreonam.
-Administer aztreonam immediately after reconstitution using an Altera Nebulizer System only. Do not administer via any other nebulizer.
-Do not mix any with any other drugs.
-Administration typically takes 2 to 3 minutes via the nebulizer mouthpiece.

Elevated hepatic enzymes due to systemic aztreonam occurs more commonly in pediatric patients versus adults. The increased incidence of these adverse effects may be due to either the increased severity of illness or the higher doses of aztreonam administered to pediatric patients. During pediatric studies, 3.8% of patients had elevated AST and 6.5% had elevated ALT. However, 15% to 20% of children less than 2 years of age who received 50 mg/kg every 6 hours experienced elevated AST and ALT to more than 3 times the upper limit of normal. In adults receiving systemic aztreonam, fewer than 1% had signs or symptoms of hepatobiliary dysfunction, hepatitis, or jaundice.

Aztreonam has been associated with gastrointestinal side effects. Diarrhea has been reported in 1.4% of pediatric patients during systemic clinical trials. Other GI side effects noted in general during clinical trials include nausea (1% to 1.3% adult systemic trials), vomiting (6% nebulized trials; 1% to 1.3% adult systemic trials), and abdominal pain (7% adult systemic trials). Abdominal cramps, GI bleeding, oral ulceration, altered taste (dysgeusia), numb tongue, and halitosis have also been reported in less than 1% of patients receiving systemic aztreonam in the general population.

Microbial overgrowth and superinfection can occur with antibiotic use. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis (less than 1%) has been reported with systemic aztreonam. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate. Other infections due to overgrowth of unsusceptible organisms may be seen during systemic aztreonam treatment including vaginal candidiasis (less than 1%).

In children, a local injection site reaction consisting of pain (1.5% to 2%), erythema (0.5% to 2.9%), induration (0.5% to 0.9%), and phlebitis (0.5% to 2.1%) occurs more frequently than in adult patients after IV administration of aztreonam.

In clinical trials of nebulized aztreonam in patients with cystic fibrosis, respiratory adverse events were the most commonly reported events; respiratory events have also been noted with systemic therapy. Cough occurred in 54% of nebulized aztreonam-treated adult and pediatric patients. Nasal congestion and wheezing were reported in 16% receiving nebulizer therapy and in less than 1% of patients receiving systemic therapy. Pharyngolaryngeal pain occurred in 12% and chest discomfort occurred in 8% with nebulizer therapy. With nebulized administration, bronchospasm was reported in 3% of patients immediately after administration; with systemic treatment, though, bronchospasm (less than 1% of adult patients) has been reported and may be related to hypersensitivity. Dyspnea, chest pain (unspecified), and sneezing have also been reported in less than 1% of adult patients receiving systemic therapy.

Rare cases of toxic epidermal necrolysis have been reported (less than 1%) in association with systemic aztreonam in adult patients undergoing bone marrow transplantation with multiple other risk factors and concomitantly receiving other drugs associated with toxic epidermal necrolysis. Rash has been reported in 4.3% of pediatric patients receiving systemic aztreonam, but has also been reported in 2% of patients receiving the inhalation product. Other dermatologic adverse events reported in the general population with systemic aztreonam in less than 1% of patients include purpura, erythema multiforme, exfoliative dermatitis, urticaria, petechiae, pruritus, and diaphoresis.

Fever (pyrexia) was noted in 13% of patients receiving nebulized aztreonam in clinical trials as compared to 6% of patients receiving placebo, and was more commonly reported in pediatric patients than in adults. In patients receiving systemic therapy, fever was also more commonly reported in pediatric patients (1%) than in adult patients (less than 1%). Other adverse effects noted in less than 1% of adult patients receiving systemic therapy include weakness, headache, malaise, and muscular aches. Increased serum creatinine was reported in 5.8% of pediatric patients.

Neutropenia due to systemic aztreonam occurs more commonly in pediatric patients versus adults. The increased incidence of these adverse effects may be due to either the increased severity of illness or the higher doses administered to pediatric patients. In pediatric trials, neutropenia (neutrophil count less than 1000/mm3) was noted 3.2% of patients and in 11.3% of children less than 2 years of age receiving aztreonam 30 mg/kg every 6 hours. Eosinophilia was reported in 6.3% and thrombocytosis was noted in 3.6% of pediatric patients during systemic trials. Other hematologic adverse events reported in less than 1% of adult patients during systemic trials include pancytopenia, thrombocytopenia, anemia, and leukocytosis.

Hypersensitivity reactions have been reported with both systemic and nebulized aztreonam therapy. Anaphylaxis/anaphylactoid reactions and angioedema have been reported in less than 1% of the general population receiving systemic therapy. Allergic reactions including facial rash, facial swelling, and throat tightness have been reported in patients with nebulized administration.

Cardiovascular adverse events reported in less than 1% of adult patients receiving systemic aztreonam therapy include hypotension, flushing, and transient ECG changes including ventricular bigeminy and premature ventricular contractions (PVCs).

Nervous system adverse events reported in less than 1% of adult patients receiving systemic aztreonam therapy include seizures, confusion, encephalopathy, vertigo, paresthesias, insomnia, and dizziness.

Adverse events of the special senses that occurred in less than 1% of adult patients receiving systemic aztreonam in clinical trials include tinnitus and diplopia.

Vaginitis and breast tenderness were reported in less than 1% of adult patients receiving systemic aztreonam in clinical trials.

A false-positive reaction for glucose in the urine has been observed in patients receiving aztreonam and using Benedict's solution, Fehling's solution, and Clinitest tablets. This reaction, however, has not been observed with Tes-tape (glucose Enzymatic Test Strip, USP, Lilly).

Aztreonam is a monocyclic beta-lactam. The incidence of allergic drug reactions to aztreonam is estimated at roughly 2% from reported clinical trial literature, and some reactions are consistent with IgE-mediated responses. Use is contraindicated in any patient with direct aztreonam hypersensitivity. The manufacturer states that aztreonam should be used cautiously in patients with sensitivity to any beta-lactam related antibiotic (e.g., penicillin hypersensitivity, cephalosporin hypersensitivity, carbacephem hypersensitivity, carbapenem hypersensitivity) due to the minor chemical structural similarities in the agents. However, in actuality, such cross-sensitive reactions to aztreonam are thought quite rare, and there is clinical evidence to support aztreonam's low potential for such events. Patients with known and established penicillin allergy who receive skin testing to determine if they will cross-react to aztreonam rarely have positive skin tests, and many such patients have received full therapeutic dosing with aztreonam without incident. Clinicians should be aware that it is certainly possible to have cross-hypersensitivity, but such reactions do not appear common.

According to the FDA-approved product labeling, parenteral aztreonam use should be limited to pediatric patients with normal renal function because of a lack of data in children with renal impairment. Aztreonam has been used in pediatric patients with renal impairment, renal failure, and even in those receiving dialysis in clinical practice; however, dosage adjustments are necessary. Because aztreonam is substantially excreted by the kidney, the risk of adverse effects and toxic reactions may be greater in patients with impaired renal function. Given the low systemic exposure after nebulization, clinically relevant accumulation is unlikely to occur. Nebulized aztreonam may be administered to patients with all degrees of renal impairment.

Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including aztreonam, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

Like with other inhaled therapies, acute bronchospasm has been associated with aztreonam solution for inhalation. Reduction of FEV1 by 15% or more immediately after administration with nebulized aztreonam was observed in 3% of patients in clinical trials despite the use of a bronchodilator prior to the administration of aztreonam. In clinical trials, patients with increased FEV1 during the 28 day treatment period were sometimes treated for pulmonary exacerbations when FEV1 declined after the 28 day treatment period. Healthcare providers should consider the patient's baseline FEV1 prior to aztreonam therapy and the presence of other symptoms when evaluating post-treatment changes in FEV1.

Systemically administered aztreonam contains 780 mg of arginine per gram of drug. Neonates and young infants may have a limited metabolic capacity to handle amino acids, such as arginine. This may result in an exaggerated response to increased plasma concentrations which may alter glucose homeostasis. Adequate glucose supplementation and monitoring is necessary to avoid hypoglycemia in these patients.

Description: Aztreonam is a synthetic monobactam beta-lactam antibiotic that is administered intravenously and via inhalation. The spectrum of activity is limited to aerobic gram-negative bacteria; it has no gram-positive or anaerobic activity. Clinical uses include skin and soft-tissue infections, urinary tract infections, respiratory tract infections, intra-abdominal infections, and gynecologic infections. Aztreonam inhalation therapy is approved to improve respiratory symptoms in cystic fibrosis in patients with Pseudomonas aeruginosa and was designated an orphan drug for the control of gram-negative bacteria in the respiratory tract in cystic fibrosis patients in March 2002 and for the improvement of respiratory symptoms in patients with bronchiectasis and gram-negative bacteria in the airways in May 2009. Aztreonam is FDA-approved in pediatric patients as young as 9 months and the inhalation therapy is approved in patients as young as 7 years.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Aeromonas hydrophila, Citrobacter freundii, Citrobacter sp., Enterobacter cloacae, Enterobacter sp., Escherichia coli, Haemophilus influenzae (beta-lactamase negative), Haemophilus influenzae (beta-lactamase positive), Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Neisseria gonorrhoeae, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens, Serratia sp., Yersinia enterocolitica
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: Salmonella enterica serotype Typhi
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of skin and skin structure infections, including burn wound infection:
-for the treatment of moderate skin and skin structure infections:
Intravenous dosage:
Neonates younger than 34 weeks gestation and 0 to 7 days*: 30 mg/kg/dose IV every 12 hours.
Neonates younger than 34 weeks gestation and 8 days and older*: 30 mg/kg/dose IV every 8 hours.
Neonates 34 weeks gestation and older and 0 to 7 days*: 30 mg/kg/dose IV every 8 hours.
Neonates 34 weeks gestation and older and 8 days and older*: 30 mg/kg/dose IV every 6 hours.
Infants 1 to 8 months*: 30 mg/kg/dose IV every 8 hours.
Infants, Children, and Adolescents 9 months to 17 years: 30 mg/kg/dose (Max: 2 g/dose) IV every 8 hours.
-for the treatment of severe or life-threatening skin and skin structure infections:
Intravenous dosage:
Neonates younger than 34 weeks gestation and 0 to 7 days*: 30 mg/kg/dose IV every 12 hours.
Neonates younger than 34 weeks gestation and 8 days and older*: 30 mg/kg/dose IV every 8 hours.
Neonates 34 weeks gestation and older and 0 to 7 days*: 30 mg/kg/dose IV every 8 hours.
Neonates 34 weeks gestation and older and 8 days and older*: 30 mg/kg/dose IV every 6 hours.
Infants 1 to 8 months*: 30 mg/kg/dose IV every 6 to 8 hours.
Infants, Children, and Adolescents 9 months to 17 years: 30 mg/kg/dose (Max: 2 g/dose) IV every 6 to 8 hours.

For the treatment of pulmonary exacerbation or improvement of respiratory symptoms in persons with cystic fibrosis:
-for the treatment of pulmonary exacerbation in persons with cystic fibrosis:
Intravenous dosage:
Infants 1 to 8 months*: 90 to 150 mg/kg/day IV divided every 6 to 8 hours; doses of 200 to 300 mg/kg/day IV divided every 6 hours may be necessary to maintain adequate serum concentrations in the treatment of pseudomonal isolates with higher MICs.
Infants and Children 9 months to 1 year: 90 to 150 mg/kg/day IV divided every 6 to 8 hours; doses of 200 to 300 mg/kg/day IV divided every 6 hours may be necessary to maintain adequate serum concentrations in the treatment of pseudomonal isolates with higher MICs.
Children and Adolescents 2 to 17 years: 150 to 200 mg/kg/day (Max: 8 g/day) IV divided every 6 to 8 hours; doses of 200 to 300 mg/kg/day (Max: 12 g/day) IV divided every 6 hours may be necessary to maintain adequate serum concentrations in the treatment of pseudomonal isolates with higher MICs.
-for the improvement of respiratory symptoms in persons with cystic fibrosis with chronic P. aeruginosa:
Respiratory (Inhalation) dosage:
NOTE: The FDA has designated aztreonam solution for inhalation as an orphan drug for control of gram-negative bacteria in the respiratory tract of patients with cystic fibrosis and for the improvement of respiratory symptoms in patients with bronchiectasis and gram-negative bacteria in the airways.
Children and Adolescents 7 to 17 years: 75 mg inhaled by nebulizer 3 times daily (at least 4 hours apart) for 28 days in alternating 28-day periods. Aztreonam inhalation solution is FDA-approved for persons with an FEV1 of 25% to 75% predicted.

For surgical infection prophylaxis*:
Intravenous dosage:
Infants, Children, and Adolescents: 30 mg/kg/dose IV as a single dose (Max: 2 g/dose) within 60 minutes prior to the surgical incision. Intraoperative redosing 4 hours from the first preoperative dose and a duration of prophylaxis less than 24 hours for most procedures are recommended by clinical practice guidelines. Clinical practice guidelines recommend aztreonam in combination with cefazolin, or for beta-lactam allergic patients, clindamycin or vancomycin, for urologic procedures involving implanted prosthesis. Aztreonam in combination with an appropriate antimicrobial with gram-positive activity (i.e., clindamycin or vancomycin) is also recommended as an alternate therapy for patients with a beta-lactam allergy undergoing gastrointestinal, biliary tract, uncomplicated appendectomy, colorectal, or abdominal transplantion procedures.

For the empiric treatment of febrile neutropenia*:
Intravenous dosage:
Infants, Children, and Adolescents: 50 mg/kg/dose (Max: 2 g/dose) IV every 6 to 8 hours, in combination with other antimicrobials, has been successfully used for the empiric treatment of febrile neutropenia in pediatric patients. Guidelines for the management of fever and neutropenia in cancer patients recommend monotherapy with an antipseudomonal beta-lactam or a carbapenem as empiric treatment in high-risk patients; addition of a second gram-negative antimicrobial agent, such as aztreonam, is recommended for patients who are clinically unstable, when a resistant infection is suspected, or for centers with high rates of resistant pathogens.

For the treatment of lower respiratory tract infections (LRTIs), including bronchitis, pneumonia, and community-acquired pneumonia:
-for the treatment of nonspecific lower respiratory tract infections (LRTIs), including pneumonia and bronchitis:
Intravenous dosage:
Neonates younger than 34 weeks gestation and 0 to 7 days*: 30 mg/kg/dose IV every 12 hours.
Neonates younger than 34 weeks gestation and 8 days and older*: 30 mg/kg/dose IV every 8 hours.
Neonates 34 weeks gestation and older and 0 to 7 days*: 30 mg/kg/dose IV every 8 hours.
Neonates 34 weeks gestation and older and 8 days and older*: 30 mg/kg/dose IV every 6 hours.
Infants 1 to 8 months*: 30 mg/kg/dose IV every 6 to 8 hours.
Infants Children, and Adolescents 9 months to 17 years: 30 mg/kg/dose (Max: 2 g/dose) IV every 6 to 8 hours.
-for the treatment of community-acquired pneumonia:
Intravenous dosage:
Adolescents: 30 mg/kg/dose (Max: 2 g/dose) IV every 6 to 8 hours for 5 to 7 days. In persons living with HIV, aztreonam is recommended as part of combination therapy for hospitalized patients at risk for P. aeruginosa.

For the treatment of quinolone-resistant severe typhoid fever*:
Intravenous dosage:
Infants, Children, and Adolescents: 50 mg/kg/dose (Max: 2 g/dose) IV every 8 hours for 7 to 14 days as an alternative in cephalosporin-allergic patients; treat for at least 7 days after defervescence.

For the treatment of intraabdominal infections, including peritonitis, appendicitis, intraabdominal abscess, and peritoneal dialysis-related peritonitis*:
-for the treatment of complicated community-acquired intraabdominal infections with adequate source control:
Intravenous dosage:
Neonates younger than 34 weeks gestation and 0 to 7 days*: 30 mg/kg/dose IV every 12 hours for 7 to 10 days.
Neonates younger than 34 weeks gestation and 8 days and older*: 30 mg/kg/dose IV every 8 hours for 7 to 10 days.
Neonates 34 weeks gestation and older and 0 to 7 days*: 30 mg/kg/dose IV every 8 hours for 7 to 10 days.
Neonates 34 weeks gestation and older and 8 days and older*: 30 mg/kg/dose IV every 6 hours for 7 to 10 days.
Infants 1 to 8 months*: 30 mg/kg/dose IV every 6 to 8 hours for 3 to 7 days as part of combination therapy. Complicated infections include peritonitis and appendicitis complicated by rupture, and intraabdominal abscess.
Infants, Children, and Adolescents 9 months to 17 years: 30 mg/kg/dose (Max: 2 g/dose) IV every 6 to 8 hours for 3 to 7 days as part of combination therapy. Complicated infections include peritonitis and appendicitis complicated by rupture, and intraabdominal abscess.
-for the treatment of uncomplicated intraabdominal infections:
Intravenous dosage:
Infants 1 to 8 months*: 30 mg/kg/dose IV every 6 to 8 hours as part of combination therapy. Antibiotics should be discontinued within 24 hours. Uncomplicated infections include acute appendicitis without perforation, abscess, or local peritonitis; traumatic bowel perforations repaired within 12 hours; acute cholecystitis without perforation; and ischemic, non-perforated bowel.
Infants, Children, and Adolescents 9 months to 17 years: 30 mg/kg/dose (Max: 2 g/dose) IV every 6 to 8 hours as part of combination therapy. Antibiotics should be discontinued within 24 hours. Uncomplicated infections include acute appendicitis without perforation, abscess, or local peritonitis; traumatic bowel perforations repaired within 12 hours; acute cholecystitis without perforation; and ischemic, non-perforated bowel.
-for the treatment of peritoneal dialysis-related peritonitis*:
Continuous Intraperitoneal dosage*:
Infants, Children, and Adolescents: 1 g/L intraperitoneal loading dose, followed by 250 mg/L in each dialysate exchange. Treat for 14 to 21 days.

For the treatment of bacteremia:
Intravenous dosage:
Neonates younger than 34 weeks gestation and 0 to 7 days*: 30 mg/kg/dose IV every 12 hours.
Neonates younger than 34 weeks gestation and 8 days and older*: 30 mg/kg/dose IV every 8 hours.
Neonates 34 weeks gestation and older and 0 to 7 days*: 30 mg/kg/dose IV every 8 hours.
Neonates 34 weeks gestation and older and 8 days and older*: 30 mg/kg/dose IV every 6 hours.
Infants 1 to 8 months*: 30 mg/kg/dose IV every 6 to 8 hours.
Infants, Children, and Adolescents 9 months to 17 years: 30 mg/kg/dose (Max: 2 g/dose) IV every 6 to 8 hours.

For the treatment of gynecologic infections, including endometritis and pelvic cellulitis:
-for the treatment of moderate gynecologic infections:
Intravenous dosage:
Adolescents: 30 mg/kg/dose (Max: 2 g/dose) IV every 8 hours.
-for the treatment of severe or life-threatening gynecologic infections:
Intravenous dosage:
Adolescents: 30 mg/kg/dose (Max: 2 g/dose) IV every 6 to 8 hours.

For the treatment of uncomplicated and complicated urinary tract infection (UTI), including cystitis and pyelonephritis:
-for the treatment of mild to moderate UTI, including cystitis:
Intravenous dosage:
Infants 2 to 8 months*: 30 mg/kg/dose IV every 6 to 8 hours.
Infants, Children, and Adolescents 9 months to 17 years: 30 mg/kg/dose (Max: 1 g/dose) IV every 8 hours.
-for the treatment of moderate to severe UTI, including pyelonephritis:
Intravenous dosage:
Neonates younger than 34 weeks gestation and 0 to 7 days*: 30 mg/kg/dose IV every 12 hours. Neonates are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Neonates younger than 34 weeks gestation and 8 days and older*: 30 mg/kg/dose IV every 8 hours. Neonates are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Neonates 34 weeks gestation and older and 0 to 7 days*: 30 mg/kg/dose IV every 8 hours. Neonates are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Neonates 34 weeks gestation and older and 8 days and older*: 30 mg/kg/dose IV every 6 hours. Neonates are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Infants younger than 2 months*: 30 mg/kg/dose IV every 6 to 8 hours. Infants younger than 2 to 3 months are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Infants 2 to 8 months*: 30 mg/kg/dose IV every 6 to 8 hours. Treat for 24 to 48 hours or until patient is clinically stable and afebrile, followed by oral antibiotics for a total duration of 7 to 14 days.
Infants, Children, and Adolescents 9 months to 17 years: 30 mg/kg/dose (Max: 1 g/dose) IV every 6 to 8 hours. Treat for 24 to 48 hours or until patient is clinically stable and afebrile, followed by oral antibiotics for a total duration of 7 to 14 days.

For the treatment of bronchiectasis*:
-for the treatment of acute exacerbations of bronchiectasis*:
Intravenous dosage:
Infants, Children, and Adolescents: 30 mg/kg/dose (Max: 2 g/dose) IV every 6 to 8 hours for 14 days with or without an aminoglycoside.
-for the eradication of first or new isolates of Pseudomonas aeruginosa in patients with bronchiectasis*:
Intravenous dosage:
Infants, Children, and Adolescents: 30 mg/kg/dose (Max: 2 g/dose) IV every 6 to 8 hours for 14 days with or without a systemic aminoglycoside or inhaled antibiotics, followed by inhaled antibiotics for 4 to 12 weeks.

Maximum Dosage Limits:
-Neonates
Younger than 34 weeks gestation and 0 to 7 days: Safety and efficacy have not been established; however, doses up to 60 mg/kg/day IV have been used off-label.
Younger than 34 weeks gestation and 8 days and older: Safety and efficacy have not been established; however, doses up to 90 mg/kg/day IV have been used off-label.
34 weeks gestation and older and 0 to 7 days: Safety and efficacy have not been established; however, doses up to 90 mg/kg/day IV have been used off-label.
34 weeks gestation and older and 8 days and older: Safety and efficacy have not been established; however, doses up to 120 mg/kg/day IV have been used off-label.
-Infants
1 to 8 months: Safety and efficacy have not been established. Doses up to 120 mg/kg/day IV have been used off-label for most infections; up to 300 mg/kg/day IV has been used in patients with cystic fibrosis.
9 to 11 months: 120 mg/kg/day IV is the FDA-approved maximum dosage; however, up to 300 mg/kg/day IV has been used in patients with cystic fibrosis. Safety and efficacy of nebulization have not been established.
-Children
1 to 6 years: 120 mg/kg/day IV is the FDA-approved maximum dosage; however, up to 300 mg/kg/day IV has been used in patients with cystic fibrosis. Safety and efficacy of nebulization have not been established.
7 to 12 years: 120 mg/kg/day (Max: 8 g/day) IV is the FDA-approved maximum dosage; however, up to 300 mg/kg/day (Max: 12 g/day) IV has been used in patients with cystic fibrosis. The maximum nebulized dosage is 225 mg/day.
-Adolescents
120 mg/kg/day (Max: 8 g/day) IV is the FDA-approved maximum dosage; however, up to 300 mg/kg/day (Max: 12 g/day) IV has been used in patients with cystic fibrosis. The maximum nebulized dosage is 225 mg/day.

Patients with Hepatic Impairment Dosing
No dosage adjustment is needed.

Patients with Renal Impairment Dosing
Dosage adjustment due to renal impairment is necessary for systemic dosage only. Nebulized aztreonam does not require dosage adjustment due to low systemic exposure.

According to the FDA-approved product labeling, there are insufficient data in pediatric patients with renal failure to determine appropriate dosage adjustments. However, other experts recommend the following dosage adjustments :
GFR 30 to 50 mL/minute/1.73 m2: No dosage adjustment necessary.
GFR 10 to 29 mL/minute/1.73 m2: 15 to 20 mg/kg/dose IV every 8 hours.
GFR less than 10 mL/minute/1.73 m2: 7.5 to 10 mg/kg/dose IV every 12 hours.

The FDA-labeled dosage adjustment in adults with renal impairment reduces the dose and maintains the fixed dosing intervals. Pediatric dosage adjustments are not defined.
CrCl more than 30 mL/minute/1.73 m2: No dosage adjustment needed.
CrCl 10 to 30 mL/minute/1.73 m2: After a normal loading dose, administer 50% of the standard dose and give at standard dosing intervals.
CrCl less than 10 mL/minute/1.73 m2: After a normal loading dose, administer 25% of the standard dose and give at standard dosing intervals.

Intermittent hemodialysis
For pediatric patients, 7.5 to 10 mg/kg/dose IV every 12 hours is recommended. The FDA-approved dosage adjustment for adult hemodialysis patients is to give the normal loading dose followed by 25% of the usual dose given at the standard dosing interval. For serious or life-threatening infections, one-eighth of the initial dose should be given after each hemodialysis session in addition to maintenance dosing. Aztreonam is cleared by hemodialysis with 27% to 58% of the dose removed.

Peritoneal dialysis
For pediatric patients, 7.5 to 10 mg/kg/dose IV every 12 hours.

Continuous renal replacement therapy (CRRT)
Administration of 100% of the aztreonam dose is recommended.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Unlike the penicillins and cephalosporins, aztreonam is a monobactam. It contains a sulfonic acid group that gives the beta-lactam of aztreonam its activity. Like the penicillins and cephalosporins, aztreonam is mainly bactericidal and inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. Penicillin-binding proteins are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. Penicillin-binding proteins vary among different bacterial species. In particular, aztreonam preferentially binds to PBP-3 of the gram-negative rods, and the sulfonic acid group assists in the acetylation of PBP-3. Since PBP-3 is responsible for formation of the septum during cell division, aztreonam's inhibition of these proteins causes elongation of the bacteria, inhibition of bacterial cell division, and breakage of the cell wall, which results in cell lysis and death. Aztreonam has no affinity for the PBPs of gram-positive organisms and poor affinity for anaerobic PBPs. In vitro, aztreonam has little ability to induce chromosomally mediated beta-lactamase production, although the selection of preexisting resistant organisms is still possible during clinical use.

The susceptibility interpretive criteria for aztreonam are delineated by pathogen. The MICs are defined for Enterobacterales and Aeromonas sp. as susceptible at 4 mcg/mL or less, intermediate at 8 mcg/mL, and resistant at 16 mcg/mL or more (based on a dosage of 1 g IV every 8 hours). The MICs are defined for P. aeurginosa and non-Enterobacterales as susceptible at 8 mcg/mL or less, intermediate at 16 mcg/mL, and resistant at 32 mcg/mL or more (based on a dosage of 1 g IV every 6 hours or 2 g IV every 8 hours for P. aeurginosa). The MICs are defined for H. influenzae and H. parainfluenzae as susceptible at 2 mcg/mL or less.

Bacterial resistance to aztreonam occurs via hydrolysis by beta-lactamase, alteration of the PBP, and decreased intracellular permeability.

Pharmacokinetics: Aztreonam is administered via nebulization, intravenously, and intramuscularly. Approximately 56-65% is protein-bound. Systemic aztreonam is distributed into most body tissues and fluids including lungs, liver, kidneys, bone, uterus, ovary, intestine, saliva, sputum, bile, as well as peritoneal, pleural, pericardial, and synovial fluids. It reaches high enough concentrations within the CSF to inhibit most Enterobacteriaceae.

Hepatic metabolism is a minor pathway of excretion. Aztreonam and the inactive metabolites are excreted primarily into the urine via tubular secretion and glomerular filtration. A small percentage (12%) is excreted in feces. The drug is also excreted in breast milk. Concomitant administration with probenecid or furosemide does not result in clinically significant increases in aztreonam serum concentrations.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intravenous Route
Peak plasma concentrations occur immediately after IV administration. Approximately 60-70% of an IV dose is recovered in the urine in 8 hours. Urinary excretion of a single dose is essentially complete 12 hours after the injection.

Intramuscular Route
Peak plasma concentrations occur within 60 minutes following an IM dose. Serum concentrations for intravenous or intramuscular doses are comparable at 1 hour (1.5 hours from start of IV infusion). Approximately 60-70% of an IM dose is recovered in the urine in 8 hours. Urinary excretion of a single dose is essentially complete 12 hours after the injection.

Inhalation Route
Sputum and plasma concentrations exhibited considerable variability between patients receiving nebulized aztreonam in clinical trials that included adults and pediatric patients. The mean sputum concentration 10 minutes after the first nebulized dose (75 mg) was 726 mcg/g. In patients receiving nebulized aztreonam 3 times daily, mean sputum concentrations 10 minutes after dose administration on days 0, 14, and 28 were 984 mcg/g, 793 mcg/g, and 715 mcg/g, respectively, indicating no drug accumulation. The mean peak plasma concentration one hour after the first nebulized dose was 0.59 mcg/ml. In one study of adults (n=12) and adolescents (n=11), median concentrations in the sputum were consistently lower at each dose studied when compared with the adult cohort, with no apparent dose-related response. Mean peak plasma concentrations in patients receiving nebulized aztreonam 3 times daily were 0.55 mcg/ml, 0.67 mcg/ml, and 0.65 mcg/ml on days 0, 14, and 28, respectively. These are low systemic concentrations compared to peak serum concentrations after an IV dose (approximately 54 mcg/ml after a 500 mg dose). Evaluation of plasma and urine concentrations indicates a low systemic absorption of nebulized aztreonam. Approximately 10% of the total nebulized dose is excreted in the urine as unchanged drug compared to 60-65% after IV administration. The half-life reported in adults is 2.1 hours.


-Special Populations
Pediatrics
Neonates
The half-life of aztreonam ranges from 2.2-9.9 hours in premature neonates and neonates and appears to shorten with increased gestational and post-natal age. The volume of distribution tends to correspond to the higher extracellular water content in these patients and generally ranges from 0.24-0.58 L/kg. One study in premature neonates had 14 patients with a mean gestational age of 27.6 weeks and mean birth weight 1060 g and an additional 16 patients with a mean gestational age of 32.4 weeks and a mean birth weight of 1639 g. The patients in this study had a higher volume of distribution that ranged from 0.64-1 L/kg.

Infants, Children, and Adolescents
In general, aztreonam pharmacokinetics in pediatric patients >= 9 months of age are comparable to adults in studies. Serum half-life ranges from 1.2-2.7 hours and the volume of distribution ranges from 0.2-0.29 L/kg.

Hepatic Impairment
The half-life of aztreonam is only slightly prolonged in patients with hepatic impairment.

Renal Impairment
Due to minimal systemic concentrations with the use of inhaled aztreonam, decreased renal function does not alter dosing. With declining renal function, the elimination half-life after systemic administration is prolonged and can increase up to 6-8 hours in patients with end-stage renal disease. In a study of 30 pediatric patients with UTIs aged 0.03-15.4 years (mean 4.2 years), pharmacokinetics were analyzed in 6 patients with normal renal function and 7 with various degrees of renal insufficiency. The half-life increased from 1 hour in patients with normal renal function to 3 hours in patients with a CrCl < 30 ml/min/1.73m2. Systemic dosages need to be adjusted accordingly. Aztreonam is removed by hemodialysis with 27-58% of the dose removed. Approximately 10% of the dose is removed by a 6 hour peritoneal dialysis dwell. Aztreonam given IV rapidly reaches therapeutic concentrations in peritoneal dialysis fluid; conversely, aztreonam administered intraperitoneally in dialysis fluid rapidly produces therapeutic serum concentrations.

Other
Cystic fibrosis
Children with cystic fibrosis tend to have a higher volume of distribution (0.25 L/kg) and shorter half-life (1.3 hours) of aztreonam as compared to populations without cystic fibrosis.