AHFS Class:

• Monobactams 8:12.07.16

Generic Name(s):

• Aztreonam

Aztreonam is a synthetic monocyclic β-lactam (i.e., monobactam) antibiotic.1,42,43,44,246,253,306

Aztreonam is used for the treatment of infections caused by susceptible gram-negative pathogens including Pseudomonas aeruginosa ; such infections include intra-abdominal infections (e.g., peritonitis), gynecologic infections (e.g., endometritis, pelvic cellulitis), lower respiratory tract infections (e.g., pneumonia, bronchitis), septicemia, skin and skin structure infections (including those associated with postoperative wounds or ulcers and burns), and complicated and uncomplicated urinary tract infections (e.g., pyelonephritis, cystitis). 1,46,47,48,161,163,166,173,175,176,177,192,222,223,231,245,253,265,266,267

Aztreonam is commercially available as a parenteral preparation for IM or IV use; the drug is also available as an inhalation solution for administration via nebulization to improve respiratory symptoms in cystic fibrosis patients with Pseudomonas aeruginosa in the lungs.306,307,308,309,310

Aztreonam has no useful activity against gram-positive bacteria or anaerobes, and therefore should not be used alone for empiric therapy in seriously ill patients if there is a possibility that the infection may be caused by gram-positive bacteria,1,48,154,164,165,176,186,202,206,211,222,223,232,241,253,266,268,276 or if a mixed aerobic-anaerobic bacterial infection is suspected.1,48,164,171,173,176,183,186,202,211,213,214,223,241,268,276 322 If potential pathogens also include gram-positive or anaerobic bacteria, an anti-infective active against such bacteria should be used concomitantly with aztreonam pending results of in vitro culture and susceptibility testing.1,48,154,164,165,171,173,176,183,186,202,206,211,213,222,223,232,241,253,266,268,276 Aztreonam has been used safely and effectively in conjunction with vancomycin, clindamycin, an aminoglycoside, erythromycin, metronidazole, or a penicillin.163,171,172,176,177,182,186,192,210,211,213,214,222,231,241,267 However, anti-infectives that have been shown to be potent inducers of β-lactamase production in gram-negative aerobes in vitro (e.g., cefoxitin, imipenem) should not be used concomitantly with aztreonam since the drugs may antagonize the antibacterial activity of aztreonam.1,253 If an aminoglycoside is used concomitantly with aztreonam, renal function should be monitored, especially if high aminoglycoside dosage is used or if concomitant therapy is prolonged.1,253

Intra-abdominal Infections

Aztreonam is used parenterally for the treatment of intra-abdominal infections (e.g., peritonitis) caused by susceptible gram-negative aerobic bacteria, including Citrobacter (including C. freundii ),1,213,214,253,267 Enterobacter (including E. cloacae ),1,173,177,213,214,253,267 E. coli ,1,173,177,213,214,253,267,281 Klebsiella (including K. pneumoniae ),1,173,213,214,253,281 Ps. aeruginosa ,1,173,213,214,253,267,281 or Serratia (including S. marcescens ).1,173,196,214,253,267

Because intra-abdominal infections generally are polymicrobial and frequently are mixed aerobic-anaerobic bacterial infections, aztreonam should not be used alone for empiric treatment of these infections.173,213,214,267 322

The Surgical Infection Society (SIS) has issued guidelines on the management of intra-abdominal infections.709 The guidelines state to use antimicrobial regimens that cover the typical gram-negative Enterobacteriaceae, gram-positive cocci, and obligate anaerobes involved in these infections.709 Aztreonam is generally recommended in treatment regimens for higher-risk patients.709 Although aztreonam has good in vitro activity against many gram-negative bacteria, the drug has relatively poor activity against extended-spectrum β-lactamase (ESBL)-producing strains of E. coli and K. pneumoniae .709 The SIS guidelines state to consider the use of aztreonam plus metronidazole and vancomycin as an option for empiric therapy in adults and children with intra-abdominal infections, but suggests that this regimen be reserved for higher-risk patients with serious β-lactam allergies.709

For the treatment of peritonitis in patients undergoing peritoneal dialysis, aztreonam has been administered intraperitoneally†.313,314,315 Some clinicians suggest that intraperitoneal administration is the preferred route for empiric antibiotic therapy unless the patient has systemic sepsis.312 An intraperitoneal regimen of vancomycin and aztreonam has been used for the treatment of peritoneal dialysis-associated peritonitis.314,315

Gynecologic Infections

Aztreonam is used parenterally for the treatment of gynecologic infections (e.g., endometritis, pelvic cellulitis) caused by susceptible gram-negative aerobic bacteria, including Enterobacter (including E. cloacae ),1,171,173,183,192,211,253 E. coli ,1,171,173,183,192,211,253 Klebsiella pneumoniae ,1,171,173,183,211,253 or P. mirabilis .1,171,173,183,192,211,253

Because gynecologic infections generally are polymicrobial and frequently are mixed aerobic-anaerobic bacterial infections, aztreonam should not be used alone for empiric treatment of these infections.171,173,183,211,213,214,267,268 321

For the treatment of endometritis, an empiric regimen active against all likely mixed aerobic and anaerobic pathogens is generally selected.321 The combination of clindamycin and gentamicin has been considered the gold standard for this type of infection; however, a regimen consisting of aztreonam plus clindamycin has been used.321

Oral or topical antibiotics (e.g., clindamycin, metronidazole) are generally used for the treatment of other common gynecologic infections (e.g., bacterial vaginosis).257

Respiratory Tract Infections

Aztreonam is used for the treatment of lower respiratory tract infections (e.g., pneumonia, bronchitis) caused by susceptible gram-negative aerobic bacteria including Enterobacter ,1,168,173,176,177,192,206,208,253,267 E. coli ,1,165,167,168,169,173,176,192,206,208,222,253,267 H. influenzae ,1,165,167,173,176,177,192,206,208,222,253,267 K. pneumoniae ,1,165,167,168,169,173,176,177,192,206,208,222,253,267 P. mirabilis ,1,167,168,173,176,192,253,267 Ps. aeruginosa ,1,165,167,168,169,173,176,177,192,206,208,222,253,267 or S. marcescens .1,165,168,173,206,208,253,267,268 The drug also has been effective for the treatment of lower respiratory tract infections caused by susceptible Citrobacter †,167,168,176,206,208,267 Hafnia †, K. oxytoca †,168 Morganella †,206,208 P. vulgaris †,165 Providencia stuartii †,192 or Moraxella catarrhalis †.165,208

Because lower respiratory tract infections frequently are caused by gram-positive and/or anaerobic bacteria, aztreonam should not be used alone for empiric treatment of these infections.1,48,164,165,176,186,202,206,208,223,235,241,253,266,268

The American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) have published a joint clinical practice guideline on the treatment of adults with community-acquired pneumonia.512 Aztreonam is included as an empiric treatment option for Ps. aeruginosa in adults with community-acquired pneumonia who are being treated in the inpatient setting.512 The guideline recommends empiric coverage for Ps. aeruginosa only if locally validated risk factors for the pathogen are present.512

IDSA also has published a clinical practice guideline on the management of adults with hospital-acquired and ventilator-associated pneumonia.750 Aztreonam is suggested as an empiric treatment option for gram-negative/antipseudomonal covera if the patient has a severe penicillin allergy and aztreonam is used instead of a β-lactam-based antibiotic, coverage for methicillin-sensitive S. aureus (MSSA) should be included.750

Cystic Fibrosis

Aztreonam also has been used alone or in conjunction with an aminoglycoside for the treatment of acute exacerbations of bronchopulmonary Ps. aeruginosa infections in some patients with cystic fibrosis.48,177,207,208,275,280 As with other anti-infective agents, a bacteriologic cure is rarely obtained and should not be expected in cystic fibrosis patients.48,177,207,208,280

Oral Inhalation via Nebulization

Aztreonam for inhalation solution (Cayston®) is used via nebulization to improve respiratory symptoms in cystic fibrosis patients 7 years of age or older with Ps. aeruginosa in the lungs.306,307,308,309,310 Safety and efficacy of aztreonam oral inhalation therapy have not been established in pediatric patients younger than 7 years of age, in patients with forced expiratory volume in 1 second (FEV₁) less than 25% or exceeding 75% of predicted values, or in patients colonized with Burkholderia cepacia .306 Aggressive management of chronic airway infections in patients with cystic fibrosis has been shown to prevent lung function decline.319 Nebulized antibiotics such as aztreonam can be used as suppressive therapy for such individuals with chronic infection or colonization with Ps. aeruginosa and/or other gram-negative organisms.319

Efficacy of aztreonam oral inhalation therapy in cystic fibrosis patients was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial.306,307 The trial enrolled 164 adults and pediatric patients 7 years of age or older with FEV₁ of 25-75% of predicted values (mean age 30 years [77% were 18 years of age or older], 43% female, 96% Caucasian, mean baseline FEV₁ 55% of predicted values).306,307 Patients were randomized in a 1:1 ratio to receive a 28-day regimen of aztreonam (75 mg 3 times daily) or volume-matched placebo (3 times daily) administered by oral inhalation via nebulization.306,307 All patients were required to take a dose of an inhaled bronchodilator (β-agonist) prior to each inhaled dose of aztreonam or placebo.306,307 Patients were receiving standard care for cystic fibrosis, including drugs for obstructive airway diseases;306,307 those who had received an anti-infective within the last 28 days were excluded.306,307 The primary efficacy end point was improvement in respiratory symptoms on the last day of oral inhalation treatment with aztreonam or placebo;306,307 respiratory symptoms also were assessed 2 weeks after completion of treatment.306,307 Changes in respiratory symptoms (e.g., cough, wheezing, sputum production) were assessed using a patient questionnaire.306,307

On the last day of oral inhalation treatment, improvement in respiratory symptoms was noted in aztreonam-treated patients relative to placebo-treated patients.306,307 Statistically significant improvements were seen in both adult and pediatric patients, but were substantially smaller in adults.306,307 At 2 weeks after completion of treatment, a difference in respiratory symptoms between treatment groups was still present, but the difference was smaller.306,307 Pulmonary function, as measured by FEV₁ (L), increased from baseline in patients treated with aztreonam and decreased in those treated with placebo.306,307 On the last day of treatment, there was a 10% difference between aztreonam-treated and placebo-treated patients in percent change in FEV₁ (L);306,307 improvements in FEV₁ were comparable between adult and pediatric patients.306 At 2 weeks after completion of treatment, the difference in FEV₁ between aztreonam-treated and placebo-treated patients had decreased to 6%.306,307

Septicemia

Aztreonam is used parenterally for the treatment of septicemia caused by susceptible gram-negative aerobic bacteria, including Enterobacter ,1,173,176,177,186,222,253,267 E. coli ,1,173,177,186,192,221,222,223,253,267 K. pneumoniae ,1,173,176,177,186,192,221,222,223,253,267 Ps. aeruginosa ,1,173,177,186,221,222,253,267 P. mirabilis ,1,186,192,253 and S. marcescens .1,186,253,267 The drug also has been effective when used parenterally in a limited number of adults for the treatment of septicemia caused by susceptible Citrobacter †267 or H. influenzae †.186,192

Aztreonam has generally been effective in either community-acquired or nosocomial septicemia known to be caused by susceptible gram-negative aerobes,173,186,192 and has been as effective as gentamicin186 or ceftazidime199 in the treatment of these infections.

The Surviving Sepsis Campaign has published guidelines on the management of sepsis and septic shock.258 The guidelines recommend immediate administration of appropriate antimicrobials in adults with possible sepsis or septic shock.258 Empiric antimicrobials with adequate coverage for likely pathogens should be selected based on the patient's risk for certain pathogens (e.g., MRSA, multidrug-resistant organisms).258

Skin and Skin Structure Infections

Aztreonam is used parenterally for the treatment of skin and skin structure infections, including those associated with postoperative wounds or ulcers and burns, caused by susceptible gram-negative aerobic bacteria, including Citrobacter ,1,173,192,222,253,267 Enterobacter ,1,173,177,192,223,253,267 E. coli ,1,173,192,253,267 K. pneumoniae ,1,173,176,177,192,222,253,267 P. mirabilis ,1,173,176,177,192,253,267 Ps. aeruginosa ,1,173,176,177,192,222,223,253,267 or S. marcescens .1,173,176,177,222,223,253,267

Aztreonam is also used as an adjunct to surgery in the management of abscesses, cutaneous infections, infections complicating hollow viscus perforations, or infections of serous surfaces caused by susceptible gram-negative aerobic bacteria.1,253

The Infectious Diseases Society of America (IDSA) has published guidelines on the management of skin and skin structure infections.543 Such infections include purulent skin and soft tissue infections (e.g., cutaneous abscesses, furuncles, carbuncles, inflamed epidermoid cysts).543 Aztreonam is not included as a potential antimicrobial of choice in these guidelines; when broad-spectrum empiric treatment is necessary for suspected polymicrobial infection, other antibiotics are generally recommended.543

IDSA also has published a clinical practice guideline for the diagnosis and treatment of diabetic foot infections.544 When empiric treatment of moderate or severe diabetic foot infections is indicated, IDSA recommends use of a broad-spectrum regimen pending results of in vitro culture and susceptibility testing.544 When probable pathogens include methicillin-resistant Staphylococcus aureus (MRSA), Enterobacteriaceae, Pseudomonas , and obligate anaerobes, IDSA recommends an empiric regimen of vancomycin used in conjunction with ceftazidime, cefepime, piperacillin/tazobactam, aztreonam, or a carbapenem.544 If aztreonam, ceftazidime, or cefepime is used in conjunction with vancomycin, the empiric regimen should also include an additional anti-infective for anaerobic coverage.544

Urinary Tract Infections

Aztreonam is used parenterally for the treatment of complicated or uncomplicated urinary tract infections (UTIs), including pyelonephritis and initial and recurrent cystitis, caused by susceptible gram-negative aerobes, including Citrobacter ,1,160,219,253,267 E. cloacae ,1,90,160,175,218,219,253 E. coli ,1,90,160,162,170,173,175,176,177,190,192,218,219,223,253,267 K. oxytoca ,1,253 K. pneumoniae ,1,90,160,170,173,175,176,177,219,222,253,267 P. mirabilis ,1,90,170,173,175,176,188,190,219,253,267 Ps. aeruginosa ,1,90,160,162,170,173,175,176,177,188,190,192,218,219,222,253,267 and S. marcescens .1,160,175,177,218,219,253 The drug also has been effective when used parenterally in a limited number of adults for the treatment of UTIs caused by susceptible E. aerogenes †,176,218 Morganella morganii †,176,218,267 P. vulgaris †,218 or Providencia †.177,218 Aztreonam has been effective in the treatment of cystitis or pyelonephritis caused by gram-negative aerobic bacteria resistant to aminopenicillins, first or second generation cephalosporins, and/or aminoglycosides.170,218

In controlled studies in men and women with UTIs, 5-14 days of aztreonam therapy was at least as effective as 5-14 days of therapy with an aminoglycoside (i.e., gentamicin, tobramycin)48,160 or a parenteral cephalosporin (i.e., cefotaxime, ceftriaxone).48,90,170,173,190,219,267 Although aztreonam therapy generally is associated with less toxicity than aminoglycoside therapy, colonization or superinfection with gram-positive bacteria (especially Enterococcus faecalis [formerly Streptococcus faecalis ]) has been reported more frequently with aztreonam than with aminoglycosides.46,90,160,164,175,188

In a controlled study in women with uncomplicated cystitis caused by E. coli , a single 1-g IM dose of aztreonam was as effective as 10 days of therapy with oral amoxicillin (250 mg 3 times daily); however, efficacy of a single dose of aztreonam in the treatment of these infections has not been established.219

Bone and Joint Infections

Aztreonam has been effective when used parenterally in adults for the treatment of bone and joint infections† caused by susceptible aerobic gram-negative bacteria, including osteomyelitis or septic arthritis, caused by susceptible Enterobacter , Escherichia coli , Klebsiella , Proteus mirabilis , Ps. aeruginosa , or Serratia marcescens .48,166,172,173,177,220,267,268,282 The drug also has been effective when used parenterally in a limited number of children for the treatment of osteomyelitis, osteochondritis, or septic arthritis caused by susceptible Ps. aeruginosa or Haemophilus influenzae †.178 An antistaphylococcal anti-infective agent (e.g., a penicillinase-resistant penicillin, vancomycin) should be used concomitantly with aztreonam if gram-positive bacteria are known or suspected to also be involved.177

The Infectious Diseases Society of America (IDSA) states that aztreonam can be considered an alternative for the treatment of native vertebral osteomyelitis† caused by Ps. aeruginosa when a drug of first choice (i.e., cefepime, meropenem, doripenem) cannot be used because the patient has severe penicillin allergy and when ciprofloxacin cannot be used because the infection is caused by a quinolone-resistant strain.590

CNS Infections

Aztreonam is a treatment option for healthcare-associated ventriculitis and meningitis† caused by susceptible aerobic gram-negative bacteria in patients with anaphylaxis or other contraindications to β-lactam therapy (including carbapenems).760 Case reports and cohort studies support the use of using aztreonam as an alternative to β-lactams in adults and children with meningitis due to Ps. aeruginosa , H. influenzae , and other Enterobacteriaceae.761,762,763,764,765,766,767

Guidelines from IDSA suggest that the choice between aztreonam and other alternatives (such as ciprofloxacin for Ps. aeruginosa or trimethoprim-sulfamethoxazole for β-lactamase-producing Enterobacteriacea) should consider local susceptibility patterns and known co-infecting organisms.760

Antimicrobial Prophylaxis in Surgery

Aztreonam has been used parenterally in conjunction with other anti-infectives for antimicrobial prophylaxis during surgery† in patients undergoing certain surgical procedures in which aerobic gram-negative bacteria are common pathogens.360,374

Some clinicians state that a regimen of vancomycin (or clindamycin) in conjunction with aztreonam can be used as an alternative regimen 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 These clinicians state that a regimen of clindamycin and aztreonam can be used as an alternative regimen in patients undergoing appendectomy, colorectal or small intestine surgery, or urologic surgery involving an implanted prosthesis.374

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

Empiric Therapy in Febrile Neutropenic Patients

Aztreonam has been used parenterally in conjunction with vancomycin (with or without amikacin) for empiric anti-infective therapy in febrile granulocytopenic adults†.180,216 Because gram-positive bacteria (especially S. epidermidis ) are being reported with increasing frequency in febrile granulocytopenic patients and because aztreonam is inactive against these organisms, an anti-infective agent active against staphylococci (e.g., vancomycin) should be used in conjunction with aztreonam if the drug is used for empiric therapy in these patients.215,268,457 Some guidelines have suggested a regimen of aztreonam and vancomycin as an alternative empiric regimen in patients with immediate-type penicillin hypersensitivity.457

Administration

Administer aztreonam by IV injection or infusion, or by deep IM injection.1,253

Aztreonam also is administered by oral inhalation via nebulization in patients with cystic fibrosis.306

Aztreonam has been administered intraperitoneally† in dialysis fluid.36,56,196 227 312,313,314,315

Parenteral

Administer IV or IM depending on the type and severity of infection, susceptibility of the causative organism, and condition of the patient.1,253

The manufacturers recommend that aztreonam be given IV (rather than IM) in patients with septicemia, localized parenchymal abscess (such as intra-abdominal abscess), peritonitis, or other severe systemic or life-threatening infection and when individual doses greater than 1 g are indicated.1,253

Inspect aztreonam solutions visually for particulate matter and discoloration prior to IV or IM administration.1,253 Discard any unused solution.1,253

When aztreonam is given IV via a common administration tubing used to administer another drug, especially one that is incompatible with aztreonam, flush the tubing before and after aztreonam administration with an IV infusion solution compatible with both drugs; do not give the drugs simultaneously.1,253 When a Y-type IV administration set is used to administer aztreonam, give careful attention to the calculated volume of aztreonam solution to ensure that the entire dose is infused.1,253

Intermittent IV Injection

For direct intermittent IV injection, reconstitute the contents of a single-dose vial labeled as containing 500 mg, 1 g, or 2 g of aztreonam by adding 6-10 mL of sterile water for injection.1,253 Shake the vial vigorously immediately after the diluent is added.1,253

Inject the appropriate dose of reconstituted solution slowly over a period of 3-5 minutes either directly into a vein or into the tubing of a compatible IV solution.1,253

Intermittent IV Infusion

For intermittent IV infusion, reconstitute a single-dose vial labeled as containing 500 mg, 1 g, or 2 g of aztreonam by adding at least 1.5, 3, or 6 mL, respectively, of sterile water for injection.1,253 Shake the vial vigorously immediately after the diluent is added.1,253 Further dilute the reconstituted solution in a compatible IV infusion solution.1,253 A volume control IV administration set may be used to add the appropriate dose of reconstituted aztreonam solution to the compatible IV infusion solution during administration; this final dilution should provide a solution with a concentration of 20 mg/mL or less.1,253

Infuse intermittent IV infusions of aztreonam over 20-60 minutes.1,253

IM Injection

For IM administration, reconstitute a single-dose vial labeled as containing 500 mg, 1 g, or 2 g of aztreonam by adding at least 1.5, 3, or 6 mL, respectively, of sterile water for injection, 0.9% sodium chloride injection, bacteriostatic water for injection (with benzyl alcohol or parabens), or bacteriostatic sodium chloride injection (with benzyl alcohol).1,253 Shake the vial vigorously immediately after the diluent is added.1,253

Administer the appropriate dose of reconstituted solution by deep IM injection into a large muscle (e.g., upper outer quadrant of the gluteus maximus, lateral part of the thigh).1,253 Aztreonam generally is well tolerated when given IM and should not be admixed with local anesthetic agents.1,253

Oral Inhalation by Nebulization

For administration by oral inhalation via nebulization, aztreonam is commercially available in a kit containing single-dose vials of lyophilized aztreonam powder for inhalation solution and single-dose ampuls of 0.17% sodium chloride diluent.306 Reconstitute the powder for inhalation solution using only the diluent provided by the manufacturer and just before it is time to administer a dose.306

Following reconstitution, administer aztreonam inhalation solution via nebulization using only an Altera^® nebulizer system.306 The manufacturer states that the reconstituted inhalation solution should not be administered using any other type of nebulizer and should not be administered IV or IM.306

Patients receiving aztreonam oral inhalation therapy should use a bronchodilator before aztreonam is administered.306 Short-acting bronchodilators can be taken between 15 minutes and 4 hours prior to each aztreonam dose.306 Alternatively, long-acting bronchodilators can be taken 0.5-12 hours prior to administration of aztreonam.306 For patients taking multiple inhaled therapies, the recommended order of administration is a bronchodilator, mucolytics, and, lastly, aztreonam.306

To prepare a dose of aztreonam inhalation solution for oral inhalation via nebulization, add the contents of a single-dose ampul of diluent provided by the manufacturer to a single-dose vial of aztreonam powder for inhalation solution.306 Swirl the vial gently until the powder has completely dissolved.306

Pour the reconstituted aztreonam inhalation solution into the handset of the Altera^® nebulizer system and turn on the unit.306 The reconstituted inhalation solution should not be mixed with any other drug in the Altera^® nebulizer handset.306

Administer the dose with the patient seated in a relaxed, upright position.306 Place the mouthpiece of the nebulizer handset into the mouth; with lips closed around the mouthpiece, the patient should breathe normally through the mouthpiece.306

A period of about 2-3 minutes usually is required to administer the complete dose of reconstituted inhalation solution via the nebulizer.306 Consult the manufacturer's labeling for additional information on how to administer aztreonam inhalation solution.306 Instructions on testing nebulizer functionality and cleaning the handset are provided in the instructions for use included with the nebulizer system.306

Compatibility

Admixtures containing aztreonam (10 or 20 mg/mL) and clindamycin phosphate (3, 6, or 9 mg/mL)49,53 or cefazolin (5 or 20 mg/mL)52 in 0.9% sodium chloride injection or 5% dextrose injection are stable for up to 48 hours at room temperature (25°C)1,49,52,53,253 or for 7 days when refrigerated at 4-5°C.1,53,253 Admixtures containing aztreonam (10 or 20 mg/mL) and ampicillin (5 or 20 mg/mL)54 in 0.9% sodium chloride injection are stable for 24 hours at room temperature (25°C) or for 48 hours when refrigerated at 4°C;1,54,253 similar admixtures of these drugs in 5% dextrose injection are stable for only 2 hours at room temperature or for 8 hours when refrigerated at 4°C.1,54,253 Admixtures containing aztreonam (10 or 20 mg/mL) and cefoxitin (10 or 20 mg/mL) in one of these diluents are stable for 12 hours at 25°C or 7 days at 4°C.51

Although many bicyclic β-lactam antibiotics (e.g., penicillins) are physically and/or chemically incompatible with aminoglycosides and can inactivate the drugs in vitro, aztreonam appears to be less likely to inactivate aminoglycosides in vitro.51,128,134 Admixtures containing aztreonam (10 or 20 mg/mL) and tobramycin (0.2 or 0.8 mg/mL) in 0.9% sodium chloride injection or 5% dextrose injection are stable for up to 48 hours at room temperature (25°C) or for 7 days at 4°C.1,51,253 The manufacturer states that similar solutions containing gentamicin (0.2 or 0.8 mg/mL) are also stable for up to 48 hours at room temperature or for 7 days when refrigerated.1,253 However, there is evidence that loss of gentamicin potency may occur with such admixtures at these storage temperatures and times; therefore, it has been suggested that solutions containing aztreonam (10 or 20 mg/mL) and gentamicin (0.2 or 0.8 mg/mL) be considered stable for only 8 hours at 25°C or for 24 hours at 4°C.51

Admixtures containing aztreonam and vancomycin hydrochloride in Dianeal^® 137 (Peritoneal Dialysis Solution) with 4.25% dextrose are stable for up to 24 hours at room temperature.1,253 At the Y-site, aztreonam (10 and 20 mg/mL) is compatible with ceftazidime-avibactam (8, 25, and 50 mg/mL).757

Aztreonam is physically and/or chemically incompatible with some drugs, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature).50,51,54,245 Aztreonam is incompatible with nafcillin sodium,1,50,245,253 and metronidazole,1,51,253 and these drugs should be administered separately.50,51,245

Dosage

Dosage and route of administration of aztreonam should be determined by the type and severity of infection, susceptibility of the causative organism, and patient condition.1,253 Do not use dosages lower than those usually recommended.1,253

For most infections, continue parenteral aztreonam treatment for at least 48 hours after the patient becomes asymptomatic or evidence of eradication of the infection has been obtained.1,253 Persistent infections may require several weeks of treatment.1,253

Parenteral Adult Dosage

General Adult Dosage

The usual adult parenteral dosage of aztreonam for the treatment of moderately severe systemic infections in adults is 1 g IV or IM or 2 g IV every 8 or 12 hours.1,253 For the treatment of severe systemic or life-threatening infections in adults, including infections caused by Pseudomonas aeruginosa , the usual adult dosage of aztreonam is 2 g IV every 6 or 8 hours.1,253

The manufacturers state that the maximum recommended IV or IM dosage of aztreonam in adults is 8 g daily.1,253

Intra-abdominal Infections

The standard dosage of aztreonam in the treatment of intra-abdominal infections is 1-2 g IV every 8 hours.709 In patients with impaired renal function, an initial dose of 1-2 g IV followed by 0.5-1 g IV every 6-12 hours is usually given.709

Urinary Tract Infections

The usual adult IV or IM dosage of aztreonam for the treatment of urinary tract infections is 500 mg or 1 g every 8 or 12 hours.1,160,161,162,177,190,253

The usual duration of aztreonam therapy for the treatment of uncomplicated urinary tract infections is 5-10 days;160,190 continue therapy for at least 10-18 days for the treatment of complicated urinary tract infections.160,162

Bone and Joint Infections

If aztreonam is used as an alternative for the treatment of osteomyelitis† caused by Ps. aeruginosa , the Infectious Diseases Society of America (IDSA) recommends that adults receive 2 g IV every 8 hours for 6 weeks.590

Antimicrobial Prophylaxis in Surgery

If aztreonam is used for antimicrobial prophylaxis in surgery†, some clinicians recommend that adults receive 2 g within 1 hour prior to initial incision.374 During prolonged procedures (longer than 4 hours) or if major blood loss occurs, administer additional intraoperative doses of aztreonam every 4 hours.374 The duration of prophylaxis should be less than 24 hours for most procedures; there is no evidence to support continuing prophylaxis after wound closure or until all indwelling drains and intravascular catheters are removed.360,374

Parenteral Pediatric Dosage

General Pediatric Dosage

The manufacturers recommend that pediatric patients 9 months of age or older with normal renal function receive aztreonam in a dosage of 30 mg/kg IV every 8 hours for the treatment of mild to moderate infections or 30 mg/kg IV every 6 or 8 hours for the treatment of moderate to severe infections.1,253 The manufacturers state that the maximum recommended dosage of aztreonam for pediatric patients is 120 mg/kg daily; however, higher dosages may be warranted in those with cystic fibrosis.1,253

A dosage of 50 mg/kg IV every 6 or 8 hours (i.e., 150-200 mg/kg daily) has been suggested by some clinicians for the treatment of infections in children with cystic fibrosis.269,270,275,276,280

Although safe use of aztreonam in neonates† has not been established, the American Academy of Pediatrics (AAP) states that neonates 7 days of age or younger may receive 30 mg/kg of aztreonam IV every 12 hours if their gestational age is less than 34 weeks or 30 mg/kg IV every 8 hours if their gestational age is 34 weeks or more.292 Neonates 8-28 days of age may receive 30 mg/kg IV every 8 hours if their gestational age is less than 34 weeks or 30 mg/kg IV every 6 hours if their gestational age is 34 weeks or more.292

For pediatric patients beyond the neonatal period, AAP recommends an aztreonam dosage of 90-120 mg/kg daily given IV or IM in 3 or 4 divided doses.292

Intra-abdominal Infections

Aztreonam dosage of 30 mg/kg IV every 6-8 hours has been used in pediatric patients >9 months of age.709 Higher doses may be reasonable in critically ill pediatric patients who may have an increased volume of distribution and/or accelerated clearance of antimicrobial agents.709

Oral Inhalation Dosage

Adult and Pediatric Dosage

When the commercially available aztreonam powder for inhalation solution is used in cystic fibrosis patients with Ps. aeruginosa in the lungs, the recommended dosage for adults and pediatric patients 7 years of age or older is 75 mg of aztreonam 3 times daily for 28 days via nebulization.306 Administer oral inhalation doses at least 4 hours apart (e.g., in the morning, after school, at bedtime).306

In clinical trials, adults and pediatric patients with cystic fibrosis have received up to 9 courses of aztreonam oral inhalation therapy; each course consisted of 28 days of aztreonam oral inhalation therapy (75 mg 3 times daily), followed by 28 days without such therapy.309,310

Intraperitoneal Dosage

If aztreonam is administered intraperitoneally† for the treatment of peritonitis in adults undergoing continuous ambulatory peritoneal dialysis (CAPD), some clinicians recommend that a 1-g loading dose of the drug be given IV followed by maintenance doses of 500 mg intraperitoneally in 2 L of dialysate every 6 hours.36,227 For empiric gram-negative coverage in the treatment of peritonitis in patients undergoing CAPD, some clinicians recommend a continuous aztreonam dosage regimen consisting of a loading dose of 1 g per L of dialysate followed by maintenance doses of 250 mg per L of dialysate.312

Special Populations

Renal Impairment

In adults with renal impairment, modify doses and/or frequency of administration of IV or IM aztreonam in response to the degree of renal impairment.1,30,33,36,203,227,253

Data are insufficient to date to make dosage recommendations for parenteral aztreonam in pediatric patients with impaired renal function.1,253

When aztreonam is administered by oral inhalation via nebulization, dosage adjustments are not necessary in adults or pediatric patients 7 years of age or older with mild, moderate, or severe renal impairment.306

Because serum creatinine concentrations alone may not be sufficiently accurate to assess the degree of renal impairment, especially in geriatric adults, the dosage of IV or IM aztreonam preferably should be based on the patient's measured or estimated creatinine clearance.1,253

Adults with creatinine clearances greater than 30 mL/minute per 1.73 m² may receive the usual adult dosage of IV or IM aztreonam.56 Adults with creatinine clearances of 10-30 mL/minute per 1.73 m² should receive an initial 1- or 2-g IV or IM loading dose of aztreonam followed by maintenance doses equal to one-half the usual dose (i.e., 250 mg, 500 mg, or 1 g) given at the usual dosage intervals.1,253 In adults with severe renal failure (creatinine clearances less than 10 mL/minute per 1.73 m²) and adults undergoing hemodialysis, follow an initial IV or IM loading dose equal to the usual dose (i.e., 500 mg, 1 g, or 2 g) with maintenance doses equal to one-fourth the usual dose (i.e., 125 mg, 250 mg, or 500 mg) given at the usual dosage intervals.1,36,253

Because aztreonam is removed by hemodialysis, patients with serious or life-threatening infections undergoing hemodialysis should receive a supplemental IV or IM dose of the drug equal to one-eighth the initial dose (i.e., 62.5 mg, 125 mg, or 250 mg) immediately after each dialysis period in addition to the recommended maintenance doses.1,30,36,253,276,277 In contrast to dosing recommendations from the manufacturer, results of a study found that aztreonam 1 g (for MICs up to 4 mg/L) or 2 g (for MICs up to 8 mg/L) administered once daily after hemodialysis had >90% probability of achieving target concentrations.758

In adults undergoing CAPD, some clinicians recommend an initial IV loading dose of aztreonam equal to the usual dose (i.e., 500 mg, 1 g, or 2 g) followed by maintenance doses equal to one-fourth the usual dose (i.e., 125 mg, 250 mg, or 500 mg) given at the usual dosage intervals.36,227

Hepatic Impairment

The serum half-life of aztreonam is only slightly prolonged in patients with hepatic impairment.1,253 Modification of usual IV or IM dosage probably is unnecessary in patients with stable primary biliary cirrhosis or other chronic hepatic disease, unless renal function also is impaired.32,56,276 Although some clinicians recommend that parenteral aztreonam dosage be decreased by 20-25% in patients with alcoholic cirrhosis, especially if long-term therapy with the drug is required,32,46,47 others state that this decrease in dosage is unnecessary unless renal function also is impaired.276,277

Geriatric Patients

Select dosage in geriatric patients with caution because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in these patients.1,253 Aztreonam is substantially eliminated by the kidneys and the risk of adverse reactions may be greater in patients with impaired renal function.1,253 Because geriatric patients are more likely to have renal impairment, monitor renal function and make appropriate dosage modifications if necessary.1,253

Contraindications

• Known hypersensitivity to aztreonam or any component of the formulation.1,253,306

Warnings/Precautions

Hypersensitivity

Treatment with aztreonam can result in hypersensitivity reactions in patients with or without prior exposure to the drug.1,53,306 In addition, hypersensitivity reactions to aztreonam (e.g., localized or urticarial rash) have occurred rarely when the drug was used in patients with a history of hypersensitivity to penicillins and/or cephalosporins.1,173,192,253,290,296,306,320 There is clinical and laboratory evidence of partial cross-allergenicity among bicyclic β-lactam antibiotics (e.g., carbapenems, cephalosporins, cephamycins, penicillins).151,157,243,248,263,289 Although cross-allergenicity between aztreonam and bicyclic β-lactam antibiotics has been reported only rarely,1,44,45,46,47,48,151,157,241,243,248,253,274,275,289,306,316,317,320 aztreonam should be used with caution in patients with a history of hypersensitivity to β-lactam antibiotics.1,253,306 Retrospective data suggest that there is a low potential for cross-reactivity with aztreonam among patients with an allergy to ceftazidime.756

In a study that included 212 individuals with documented immediate (IgE-mediated) hypersensitivity to penicillins who had positive skin test reactions to at least 1 penicillin reagent, all individuals had negative skin test reactions to aztreonam; there was no reaction to aztreonam in 211 of these individuals who were willing to receive an IM aztreonam challenge.317 In another study that included 214 individuals with nonimmediate (T cell-mediated) hypersensitivity to penicillins who had positive patch and/or delayed-reading skin test responses to at least 1 penicillin reagent, all individuals had negative skin test reactions to aztreonam and all tolerated IM aztreonam challenges.316 Studies in rabbits and humans suggest that antibodies produced in response to penicillin G (including IgE antibodies to major and minor determinants)1,151,157,241,243,248,274 show negligible cross-reactivity with aztreonam. Likewise, antibodies produced in response to aztreonam have had negligible cross-reactivity with penicillin G,157,241,243,248,274 , cephalothin1,243,248 and cefotaxime.241,248 In one study in healthy men who had not previously received aztreonam, no IgE antibody response to aztreonam was detectable after therapy with the drug (500-mg or 1-g doses every 8 hours for 7 days).157,243,248 A few of these individuals did have naturally occurring side-chain-specific IgG antibodies to aztreonam, but only one demonstrated an IgG response to the drug.48,157,243,248

Prior to initiation of aztreonam, assess whether the patient has had a previous hypersensitivity reaction to β-lactam antibiotics, other drugs, or allergens.1,253,306

If a hypersensitivity reaction occurs during aztreonam therapy, discontinue the drug and initiate appropriate therapy (e.g., vasopressors, antihistamines, corticosteroids, maintenance of ventilation).1,253,306 Serious hypersensitivity reactions may require the use of epinephrine and other emergency measures.1,253

C. difficile-associated Diarrhea and Colitis

C. difficile infection (CDI) and C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with nearly all systemic anti-infectives, including aztreonam, and may range in severity from mild diarrhea to fatal colitis.1,302,303C. difficile produces toxins A and B, which contribute to the development of CDAD; hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1,302,303

CDAD should be considered in the differential diagnosis of patients who develop diarrhea during or after parenteral aztreonam therapy.1,253,302,303 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1,253,302,303 If CDAD is suspected or confirmed, discontinue anti-infective therapy not directed against C. difficile whenever possible.1,253,302,303 Manage patients with appropriate supportive therapy (e.g., fluid and electrolytes management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.1,253,302,303 Other causes of colitis also should be considered.1,253

Advise patients that diarrhea is a common problem caused by systemic anti-infectives and usually ends when the drug is discontinued; however, it is important to contact a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.1,253

Toxic Epidermal Necrolysis

Toxic epidermal necrolysis has been reported rarely when parenteral aztreonam was used in patients undergoing bone marrow transplantation; these patients had multiple risk factors, including sepsis, radiation therapy, and concomitant treatment with drugs associated with toxic epidermal necrolysis.1

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of parenteral aztreonam and other antibacterials, use aztreonam only for the treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.1,253

When selecting or modifying anti-infective therapy, consider results of culture and in vitro susceptibility testing.1,253 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1,253 Culture and susceptibility testing performed periodically during therapy provides information on the therapeutic effect of the anti-infective agent and the possible emergence of bacterial resistance.1,253

Patients should be advised to only use antibacterials (including aztreonam) to treat bacterial infections and not to treat viral infections (e.g., the common cold).1,253 Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing 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

Because aztreonam has little or no activity against gram-positive bacteria and anaerobes, use another anti-infective active against such bacteria concomitantly if aztreonam is used empirically in infections that may involve gram-positive bacteria or anaerobes (e.g., gynecologic, intra-abdominal, or respiratory tract infections).1,171,173,183,211,213,214,253

Overgrowth of Nonsusceptible Organisms

As with other anti-infective agents, use of parenteral aztreonam may result in overgrowth of nonsusceptible organisms, especially gram-positive bacteria (e.g., enterococci, Staphylococcus aureus , Streptococcus pneumoniae ) or fungi.1,48,90,160,163,164,168,170,173,175,176,177,179,186,188,199,205,218,220,221,253,256,265,266,267 Colonization or superinfection with aztreonam-resistant organisms has occurred in up to 60% of patients receiving the drug,90,148,160,173,175,176,186,199,221,256,267 and superinfections have required treatment with another anti-infective agent in about 4-11% of patients.48,148,173 Use of indwelling catheters or the presence of tracheotomy sites or open, draining wounds appears to contribute to the occurrence of superinfections during aztreonam therapy.176,188,205,220,221,265,266 Resistant strains of some organisms (e.g., Pseudomonas aeruginosa , Klebsiella pneumoniae ) have developed during parenteral aztreonam therapy.165,168,176,207,218 If superinfection occurs, institute appropriate therapy.1,253

Precautions Related to Oral Inhalation Therapy

Aztreonam powder for inhalation solution should only be used to treat patients with cystic fibrosis who are known to have Ps. aeruginosa in the lungs.306 Use of aztreonam oral inhalation therapy in the absence of known Ps. aeruginosa infection is unlikely to provide benefit and increases the risk of development of drug-resistant bacteria.306

Clinicians should consider that bronchospasm is a known complication associated with nebulized therapies, including aztreonam inhalation solution.306 In clinical trials in patients pretreated with a bronchodilator, a reduction of 15% or more in FEV₁ was reported in 3% of patients immediately following administration of a dose of aztreonam inhalation solution administered by oral inhalation via nebulization.306

In clinical trials, patients with increases in FEV₁ during a 28-day course of aztreonam oral inhalation therapy were sometimes treated for pulmonary exacerbations when FEV₁ declined after the treatment period.306 When evaluating whether a change in FEV₁ after treatment is caused by a pulmonary exacerbation, consider the patient's baseline FEV₁ measured prior to initiation of aztreonam oral inhalation therapy and the presence of other symptoms.306

Specific Populations

Pregnancy

There are no adequate and controlled studies to date using parenteral aztreonam or aztreonam administered by oral inhalation via nebulization in pregnant women.1,253,306 Use parenteral or orally inhaled aztreonam during pregnancy only when clearly needed.1,253,306 Aztreonam crosses the placenta in pregnant women and enters fetal circulation.1,253,306

No evidence of embryotoxicity, fetotoxicity, or teratogenicity was found in reproduction studies in pregnant rats and rabbits using daily parenteral aztreonam dosages up to 1.8 and 1.2 g/kg, respectively;1,253 these aztreonam dosages were 2.2- and 2.9-fold greater than the maximum recommended human dosage (MRHD) based on body surface area.1,253 There was no evidence of drug-induced changes in any maternal, fetal, or neonatal parameters when parenteral aztreonam was used in a perinatal/postnatal study in rats;1,253 the highest dosage used in this study (1.8 g/kg daily) was 2.2 times the MRHD based on body surface area.1,253 However, in a 2-generation reproduction study in rats using parenteral aztreonam dosages up to 2.4 g/kg daily (2.9-fold greater than the MRHD), there was a slightly reduced survival rate during the lactation period in offspring of rats that received the highest dosage, but not in offspring of rats that received lower dosages.1

Lactation

Because aztreonam is distributed into milk in low (<1%) concentrations following parenteral administration and because safety of aztreonam in neonates has not been fully evaluated to date, consider temporary discontinuance of nursing if parenteral aztreonam is used in lactating women.1,253

Aztreonam 75 mg administered by oral inhalation via nebulization in lactating women produced peak plasma concentrations approximately 1% of peak plasma concentrations reported following a 500-mg IV dose of the drug.306 Systemic absorption of aztreonam following inhaled administration is likely minimal, but the effects on the infant or on milk production are unknown.306

Pediatric Use

The manufacturers state that use of IV aztreonam in children 9 months of age or older is supported by evidence from adequate and well-controlled studies in adults and additional efficacy, safety, and pharmacokinetic data from noncomparative clinical studies in pediatric patients.1,253 However, data are insufficient to date to determine safety and efficacy of IV aztreonam in pediatric patients 9 months of age or older for the treatment of septicemia or skin and skin structure infections (when skin infection suspected or known to be caused by Haemophilus influenzae type b).1,253 In addition, the manufacturers state that data are insufficient to date to evaluate IM administration of aztreonam in pediatric patients or use of the drug in pediatric patients with impaired renal function.1,253

In clinical studies evaluating parenteral aztreonam in pediatric patients, discontinuance of the drug because of adverse effects was required in less than 1% of patients.1 Rash, diarrhea, and fever have been reported in 1-4.3% of pediatric patients.1,253 In pediatric patients receiving IV aztreonam, pain was reported in 12% and erythema, induration, or phlebitis were reported in 0.9-2.9% of patients overall; in US patients, pain occurred in 1.5% and other local reactions occurred in about 0.5%.1,253 Eosinophilia, neutropenia, or increased platelet count has been reported in 6.3, 3.2, or 3.6% of pediatric patients, respectively, and increased serum AST, ALT, or serum creatinine has been reported in 3.8-6.5%.1,253 In US pediatric studies, neutropenia (absolute neutrophil count less than 1000/mm³) occurred in 11.3% of patients younger than 2 years of age receiving aztreonam in a dosage of 30 mg/kg every 6 hours and increased serum AST and ALT (greater than 3 times the upper limit of normal) occurred in 15-20% of patients 2 years of age or older receiving a dosage of 50 mg/kg every 6 hours.1,253 It is unclear whether the increased frequency of these adverse effects was related to increased severity of illness in the patients or aztreonam dosage administered.1,253

Aztreonam has been used IM or IV in a limited number of neonates and infants as young as 1 month of age† without unusual adverse effects.1,5,15,177,178,179,194,253,256,275,280

Safety and efficacy of aztreonam administered by oral inhalation via nebulization have not been established in pediatric patients younger than 7 years of age.306 The drug has been used by oral inhalation via nebulization for the treatment of newly acquired Ps. aeruginosa respiratory tract infections in a limited number of cystic fibrosis patients 3 months through 6 years of age† without unusual adverse effects.318 In clinical trials evaluating aztreonam inhalation therapy in cystic fibrosis patients 7 years of age or older, pyrexia was reported more frequently in pediatric patients than in adults.306

Geriatric Use

Clinical studies evaluating IV or IM aztreonam or aztreonam administered by oral inhalation via nebulization did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger patients.1,253,306 Other reported clinical experience with parenteral aztreonam has not identified differences in responses between geriatric patients and younger adults.1,253

Aztreonam is substantially eliminated by the kidneys, and the risk of adverse effects may be greater in those with impaired renal function.1,253 Because geriatric patients are more likely to have reduced renal function, select IV or IM dosage of aztreonam with caution and monitor renal function.1,253

Hepatic Impairment

Monitor appropriate laboratory tests when aztreonam is used in patients with impaired hepatic function.1,253,276,277 Some clinicians suggest that liver function tests (i.e., serum hepatic enzyme concentrations) be determined once weekly in patients receiving IV or IM aztreonam; however, the manufacturer and other clinicians question the necessity of this precaution.266,267

Renal Impairment

Monitor appropriate laboratory tests when aztreonam is used in patients with impaired renal function.1,253,276,277 Decrease doses and/or frequency of administration of IV or IM aztreonam in patients with impaired renal function, since serum concentrations of the drug are higher and prolonged in these patients compared with patients with normal renal function.1,2,11,30,33,36,46,47,48,56,203,227,253,256

Common Adverse Effects

Adverse effects reported with IV or IM aztreonam are similar to those reported with other β-lactam antibiotics, and the drug generally is well tolerated.47,48,166,173,206,218,241,256,267 Adverse effects have been reported in 7% or less of patients receiving parenteral aztreonam1,205,253,265 and have required discontinuance in about 2% of patients.48,173,205,265

Drug interactions reported are based on parenteral aztreonam.1,253 Formal drug interaction studies have not been conducted to date using aztreonam administered by oral inhalation via nebulization.306

Antibacterial Agents

Aminoglycosides

In a study in healthy adults who received a single 1-g IV dose of aztreonam concomitantly with a single 80-mg IV dose of gentamicin, peak serum concentrations of aztreonam were decreased by about 13%, but other pharmacokinetic parameters of the drugs (e.g., half-lives, AUCs) were not affected by concomitant administration.154 This was not considered clinically important.1,253 Further study using multiple doses of the drugs and/or higher doses is probably needed to confirm that there are no clinically important pharmacokinetic interactions between aztreonam and gentamicin.154,195

The antibacterial activity of aztreonam and aminoglycosides is additive or synergistic in vitro against most strains of Pseudomonas aeruginosa 1,38,48,57,78,88,107,111,112,128,131,140 and some strains of Ps. cepacia ,48,107,131 Ps. fluorescens ,131 and Ps. maltophilia .131 The combination of aztreonam and an aminoglycoside also is synergistic against some Enterobacteriaceae, including some strains of Enterobacter , Escherichia coli , Klebsiella , and Serratia .1,57,78,88,140

In vitro, the combination of aztreonam and an aminoglycoside has occasionally been synergistic against Acinetobacter , although the combination more frequently is only additive or indifferent against this organism.131

The combination of aztreonam and an aminoglycoside generally is indifferent against gram-positive bacteria, including Staphylococcus aureus , S. epidermidis , and Enterococcus faecalis (formerly Streptococcus faecalis ).88,92,131

-Lactam Antibiotics

In a single-dose IV study, there were no clinically important pharmacokinetic interactions between nafcillin sodium and aztreonam.1,253

An additive or synergistic effect has occurred in vitro against some strains of Ps. aeruginosa when aztreonam was used concomitantly with piperacillin78 or cefotaxime.78 The combination of aztreonam and ampicillin,77 piperacillin,78 or cefotaxime78 generally is indifferent or only slightly additive against Enterobacteriaceae, including Enterobacter , E. coli , S. marcescens , and Klebsiella .78,92

In vitro, the combination of aztreonam and cefoxitin has been synergistic against some strains of Enterobacter , E. coli , Klebsiella , S. marcescens , Salmonella , and Shigella .77 However, antagonism has occurred in vitro when aztreonam was used in combination with cefoxitin against Enterobacter or S. marcescens .77,127 Antagonism also has occurred in vitro when imipenem was used in combination with aztreonam against Ps. aeruginosa .92 Antagonism between aztreonam and these anti-infectives may occur because cefoxitin and imipenem are potent β-lactamase inducers and can derepress inducible, chromosomally mediated β-lactamases in gram-negative bacteria that possess these enzymes (e.g., Enterobacter , Serratia , Ps. aeruginosa ).77,127,195 Although aztreonam is relatively stable against hydrolysis by inducible β-lactamases, it has been suggested that the enzymes may inactivate aztreonam by binding to the drug and preventing access to penicillin-binding proteins (PBPs).77,127,195 Because the combinations may be antagonistic, anti-infective agents that are potent inducers of β-lactamase production (e.g., cefoxitin, imipenem) should not be used concomitantly with aztreonam.1

Chloramphenicol

Results of an in vitro study using K. pneumoniae indicate that chloramphenicol can antagonize the bactericidal activity of aztreonam.139 It has been suggested that if concomitant use of the drugs is indicated, chloramphenicol should be administered a few hours after aztreonam; however, the necessity of this precaution has not been established.139

Clindamycin

In a study in healthy adults who received a single IV dose of aztreonam concomitantly with a single IV dose of clindamycin, total urinary excretion of aztreonam was increased by about 5%.154 This was not considered clinically important,1,154 and other parameters (e.g., half-lives, AUCs) were not affected by concomitant administration of the drugs.154 Further study using multiple and/or higher doses of the drugs probably are needed to confirm that there are no clinically important pharmacokinetic interactions between aztreonam and clindamycin.154,195

In vitro, the antibacterial activity of aztreonam and clindamycin has been synergistic against some strains of E. coli , Klebsiella , and Enterobacter , although the combination more frequently is indifferent or additive against these organisms.77 Indifferent or slightly additive effects also have been reported when aztreonam was used in conjunction with clindamycin against anaerobic bacteria.38

Metronidazole

In a study in healthy adults who received a single IV dose of aztreonam concomitantly with a single IV dose of metronidazole, peak serum concentrations of aztreonam were decreased by about 10%.154 This was not considered clinically important,1,154 and other parameters (e.g., half-lives, AUCs) were not affected by concomitant administration of the drugs.154 Further study using multiple and/or higher doses of the drugs probably are needed to confirm that there are no clinically important pharmacokinetic interactions between aztreonam and metronidazole.154,195

In vitro, indifferent or slightly additive effects have been reported when aztreonam was used in conjunction with metronidazole against anaerobic bacteria.38

Clavulanic Acid

In vitro studies indicate that the combination of aztreonam and clavulanic acid, a β-lactamase inhibitor, is synergistic against some strains of β-lactamase-producing Enterobacter ,48 Klebsiella ,48 and Bacteroides fragilis 88,234 resistant to aztreonam alone.234 The combination of aztreonam and clavulanic acid may also be antagonistic against some organisms.127,276 Clavulanic acid can induce production of chromosomally mediated β-lactamases in some gram-negative bacteria (e.g., Enterobacter , Ps. aeruginosa ) and therefore could interfere with the antibacterial activity of aztreonam by a mechanism similar to that seen with cefoxitin or imipenem.127,279 Concomitant use of clavulanic acid and aztreonam does not alter the in vitro susceptibility of S. aureus to aztreonam since resistance to the drug in these organisms is intrinsic.234

Furosemide

Concomitant use of furosemide can increase serum concentrations of aztreonam, but this effect is not considered clinically important.1,253

Probenecid

Concomitant use of probenecid slows the rate of renal tubular secretion of aztreonam and can increase serum concentrations of aztreonam.1,2,34,56,253 This effect, however, is not sufficient to be of therapeutic benefit1,2,34,56,253 since it produces only a 5% increase in serum aztreonam concentrations and an 11% increase in the serum half-life of the drug.34 Concomitant probenecid also appears to decrease the binding of aztreonam to plasma proteins by about 13%, presumably by competing with the drug for plasma and tissue protein binding sites, and decreases the steady-state volume of distribution of aztreonam by about 16%.34

Pharmacology

Description

Aztreonam is a synthetic monobactam antibiotic.1,42,43,44,246,253,306

Like bicyclic β-lactam antibiotics, the antibacterial activity of aztreonam results from inhibition of mucopeptide synthesis in the bacterial cell wall.1,38,46,57,59,60,247,253 Aztreonam has a high affinity for and preferentially binds to penicillin-binding protein 3 (PBP 3) of susceptible gram-negative bacteria.38,44,46,47,48,57,59,60,76,127,137,247 The drug also has some affinity for PBP 1a of these bacteria,44,57,59,60,76,137,247 but little or no affinity for PBPs 1b, 2, 4, 5, or 6.44,57,59,60,76,137,247 Because PBP 3 is involved in septation, aztreonam causes the formation of abnormally elongated or filamentous forms in susceptible gram-negative bacteria.38,44,47,48,57,59,60,113,137,142,247 As a consequence, cell division is inhibited and breakage of the cell wall occurs resulting in lysis and death.38,57,113 Studies using Staphylococcus aureus 44,59,60 indicate that aztreonam does not bind to the essential PBPs of gram-positive bacteria.3,38,40,44,46,47,57,59,60 Aztreonam also has poor affinity for the PBPs of anaerobic bacteria.3,38,40,46,47,57,59,146 The drug, therefore, generally is inactive against these organisms.3,38,44,57,59,146

Aztreonam usually is bactericidal in action.1,46,48,55,67,88,137,253 Since aztreonam has poor affinity for PBPs 1a and 1b of susceptible gram-negative bacteria, it is not as rapidly bactericidal as some other β-lactam antibiotics (e.g., imipenem, cefotaxime, cefoxitin, ceftriaxone) against these organisms.137,142,247 For most susceptible Enterobacteriaceae, the minimum bactericidal concentration (MBC) of aztreonam is equal to or only 2-4 times higher than the minimum inhibitory concentration (MIC) of the drug.38,46,48,57,69,70,77,78,88,96,129,138 For Pseudomonas aeruginosa , the MBC of aztreonam is usually only 2 times higher than the MIC,48,96,111,112,129,138 but may be up to 125 times higher than the MIC for some strains of the organism.48,141

Spectrum

Aztreonam has a narrow spectrum of activity.38,40,44,46,55,57,59,76,77,83,85,96,234,241 The drug is active in vitro against many gram-negative aerobic bacteria, including most Enterobacteriaceae and Pseudomonas aeruginosa,1,3,38,39,40,44,46,47,48,55,57,59,69,70,76,83,84,85,96,234,241,253,280 but has little or no activity against gram-positive aerobic bacteria3,38,39,40,44,46,47,48,55,57,59,69,70,73,75,76,83,84,85,96,234,241 or against anaerobic bacteria.3,38,39,40,44,46,47,48,55,57,59,69,70,73,75,76,83,84,96,97,241 Aztreonam is inactive against Chlamydia89,278 Mycoplasma, fungi, and viruses.276,277

Resistance

Aztreonam has a high degree of stability against hydrolysis by bacterial β-lactamases, including both plasmid-mediated and chromosomally mediated enzymes, and retains activity in the presence of some penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria.44,48,55,57,67,68,76,83,84,88,98,233,241 The drug generally is more stable against inactivation by β-lactamases than cefotaxime.55,84 Aztreonam generally is stable against hydrolysis by β-lactamases classified as Richmond-Sykes types I,48,67,98 III (TEM-1, TEM-2, SHV-1),44,48,55,67,76,98 and V (PSE and OXA types).44,48,67,76,98 The drug is stable against hydrolysis by most chromosomally mediated Richmond-Sykes type I enzymes produced by Citrobacter, Enterobacter, Morganella, Proteus, Providencia, Serratia, and Proteus.44,67,83,84,98,233 The drug also is stable against hydrolysis by staphylococcal β-lactamases48,67 and most β-lactamases produced by Bacteroides.44,57,76

Aztreonam in combination with other β-lactams or β-lactam/β-lactamase inhibitors (such as ceftazidime-avibactam) has shown synergistic efficacy against metallo-β-lactamase, serine-β-lactamase, and extended-spectrum β-lactamase-producing organisms, including Enterobacteriaceae751 and other Enterobacterales species,752 K. pneumoniae 753,754 and Ps. aeruginosa 755,756

Aztreonam is hydrolyzed by a chromosomally mediated Richmond-Sykes type IV enzyme (K-1) produced by some strains of Klebsiella oxytoca,38,44,48,57,67,68,76,83,87,88,98,130,233 and strains that produce this enzyme generally are resistant to the drug.38,44,48,98 Aztreonam also is hydrolyzed to some extent by PSE 2, a Richmond-Sykes type V plasmid-mediated β-lactamase produced by Ps. aeruginosa;44,48,57,67,76,83,87,98,233 the drug generally is stable against hydrolysis by PSE 1, 3, and 4.44,48,67,76,98 A chromosomally mediated β-lactamase produced by Bacteroides (B1) can also slowly hydrolyze aztreonam.44,76

In vitro studies indicate that aztreonam is a poor inducer of β-lactamase production and generally does not derepress inducible, chromosomally mediated enzymes in gram-negative bacteria that possess these enzymes (e.g., some strains of Pseudomonas, Citrobacter, Enterobacter, and Serratia).1,38,57,150,238 Although aztreonam is relatively stable against hydrolysis by inducible β-lactamases, it has been suggested that the enzymes may inactivate the drug by binding to it and preventing access to penicillin-binding proteins (PBPs).57,77,127,195,238 Therefore, gram-negative bacteria that possess these inducible β-lactamases may be resistant to aztreonam following derepression of the enzymes.57,132,150

Resistance to aztreonam has been produced in vitro in some strains of E. cloacae initially susceptible to the drug,229,238 and aztreonam-resistant strains of the organism have emerged during aztreonam therapy.147 E. cloacae resistant to aztreonam may also be resistant to third generation cephalosporins and extended-spectrum penicillins,147,229,237,238 but may be susceptible to imipenem.229,237,238 Aztreonam resistance in some strains of E. cloacae appears to be related to alterations in outer-membrane porin proteins and/or other factors that affect permeability of the organism to the drug.57,237,238

Pharmacokinetics

Aztreonam exhibits linear, dose-independent pharmacokinetics.4,6,10,29 The pharmacokinetics of the drug after IV administration are best described by an open, linear, 2-compartment model and pharmacokinetics after IM administration are best described by an open, one-compartment model with first-order absorption and elimination.4,6,7,10,29,46,47,212 The pharmacokinetics of aztreonam in pediatric patients 9 months of age or older are similar to those in adults.1 Aztreonam is rapidly and completely absorbed following IM administration,2,6,7,29,46,47,48,56,256 and peak serum concentrations of the drug generally are attained within 1 hour after an IM dose.1,2,6,7,29,46 Although peak serum concentrations of aztreonam attained with an IM dose are slightly lower than those attained with an equivalent IV dose, serum aztreonam concentrations 1 hour or longer after dosing are similar.1,2

Multiple-dose studies in adults with normal renal and hepatic function receiving an IM or IV aztreonam dosage of 0.5-1 g every 8 hours for 7 days indicate that neither peak nor trough serum concentrations of the drug increase after repeated dosing and that the drug does not accumulate.1,2,6,7,10,12,46,48,56 10

Data from adults and pediatric patients with cystic fibrosis indicate that variable concentrations of aztreonam enter systemic circulation when the drug is administered by oral inhalation via nebulization, but accumulation does not occur following multiple doses.306,307,308

Aztreonam is widely distributed into body tissues and fluids following IM or IV administration.21,46,48 At serum concentrations of 1-100 mcg/mL,6,10,234 aztreonam is 46-60% bound to serum proteins in healthy adults.1,2,6,10,14,33,34,48,56,234 In adults with impaired renal function and decreased serum albumin concentrations, aztreonam is 22-49% bound to serum proteins.13,33,46,48 Aztreonam crosses the placenta and is distributed into amniotic fluid.1,28,46,48,56 The drug is distributed into milk in low concentrations.1,27,46,48,56 In lactating women who received a single 1-g IM or IV dose of aztreonam, peak milk concentrations were attained 2-6 hours after the dose.27

When aztreonam is administered by oral inhalation via nebulization in adult and pediatric patients with cystic fibrosis, sputum concentrations of the drug exhibit considerable interindividual variation, but accumulation does not occur following multiple doses.306,307,308

Aztreonam is partially metabolized to several microbiologically inactive metabolites;2,6,7,17,33,46,48,56 no active metabolites of the drug have been found in serum or urine.2,6,7,17,29,48,56 The principal metabolite of aztreonam, which is formed by nonspecific hydrolysis of the β-lactam ring, is 2-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy) imino]acetyl]amino]-3-(sulfoamino)butanoic acid30 (SQ 26,992).2,6,7,15,30,46,48,56 Other inactive metabolites, which have not been identified, reportedly may be demethylated products of SQ 26,992.

Serum concentrations of aztreonam decline in a biphasic manner after IV administration.2,4,6,7,9,10,14,23,29,33,34,46,47,48,56 In adults with normal renal and hepatic function, the distribution half-life (t_½α) of aztreonam averages 0.2-0.7 hours2,4,6,7,9,10,14,29,33,46,48,56 and the elimination half-life (t_½β) averages 1.3-2.2 hours.1,2,4,6,7,9,10,14,23,29,33,34,46,47,48,56 The t_½β of SQ 26,992 is longer than that of aztreonam and is about 26 hours in adults with normal renal and hepatic function.1,7,48

In geriatric adults, renal clearance of aztreonam is decreased and the t_½ of the drug is prolonged compared with younger adults.1,14,90,266 The t_½β of aztreonam ranges from 1.7-4.3 hours in adults 64-82 years of age with renal function normal for their age.14,90,266

The t_½β of aztreonam averages 1.7 hours in children 2 months to 12 years of age.15 Half-life of the drug is longer in neonates than in older children and adults and is inversely related to age and birthweight.15 In neonates younger than 7 days of age, t_½β of aztreonam averages 5.5-9.9 hours in those weighing less than 2.5 kg5,15 and 2.6 hours in those weighing more than 2.5 kg.15 In neonates 1 week to 1 month of age, t_½β of the drug averages 2.4 hours.15

In patients with renal impairment, serum concentrations of aztreonam are higher and the serum half-life prolonged.1,2,30,33,46,47,48,56,203,212

In patients with hepatic impairment, serum half-life of aztreonam is only slightly prolonged since the liver is a minor pathway of elimination for the drug.1 In a study in patients with cirrhosis but with normal renal function, the t_½β of aztreonam averaged 2.2 hours in those with primary biliary cirrhosis and 3.2 hours in those with alcoholic cirrhosis.32

Aztreonam is excreted 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 Following IM or IV administration of a single 0.5-, 1-, or 2-g dose of aztreonam in adults with normal renal function, approximately 58-74% of the dose is excreted in urine unchanged,1,2,3,4,6,7,14,23,33,46,48,56 1-7% is excreted as SQ 26,992,1,2,6,7,14,23,33,48,56 and 3-4% is excreted as unidentified inactive metabolites.2,48 Urinary excretion of unchanged aztreonam is essentially complete 8-12 hours after a single dose of the drug,1,4,6,7,10,14,29,34 but SQ 26,992 is excreted for up to 48 hours after the dose.7,10,14

Aztreonam is partially excreted in feces,1,2,7,46,48,56,152 presumably via biliary elimination.2,7,23,46,48,56 Approximately 1% of a single 500-mg IV dose of the drug is 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

Cystic fibrosis patients may eliminate aztreonam at a faster rate than healthy individuals.46,48,177,269,270 Serum half-life of the drug averaged 1-1.3 hours in several patients with cystic fibrosis.177,269,270 177

Aztreonam2,30,36,46,47,177,203,256 and SQ 26,992203 are removed by hemodialysis. The amount of the drug and its metabolites removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow rate).36,203 In one group of patients with end-stage renal disease undergoing hemodialysis, the serum half-life of aztreonam averaged 2.7 hours during hemodialysis and 7.9 hours between dialysis sessions.2 A 4-hour period of hemodialysis generally removes into the dialysate about 27-58% of a single 1-g IV dose of aztreonam when the dose is given 1 hour prior to dialysis.36

Aztreonam is removed to a lesser extent by peritoneal dialysis.1,36,47,227 In patients with chronic renal failure undergoing CAPD with a 6-hour dwell time, about 10% of a single 1-g IV dose of aztreonam is removed into the dialysate within 48 hours after the dose.36,37,47,227

When the commercially available aztreonam powder for inhalation solution is administered by oral inhalation via nebulization, approximately 10% of the total dose is excreted unchanged in urine;306 glomerular filtration and tubular secretion are equally involved in elimination of systemically absorbed drug.306

In adults with cystic fibrosis receiving aztreonam by oral inhalation via nebulization, the plasma elimination half-life of systemically absorbed drug is approximately 2.1 hours.306

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
• Advise patients to complete the full course of therapy, even if feeling better after a few days.1,253
• 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
• Advise patients to discontinue therapy and inform their clinician if an allergic reaction occurs.1,253
• Advise patients that diarrhea is a common problem caused by systemic anti-infectives and usually ends when the drug is discontinued.1,253 Advise patients to contact 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
• 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; 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 a possible allergic reaction occurs.306
• Advise patient to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1,253,306
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1,253 306
• Inform patients of other important precautionary information.1,253,306

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Bristol-Meyers Squibb. Azactam^® (aztreonam) for injection prescribing information. Princeton, NJ; 2021 Mar.

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