aztreonam 1000 MG Injection

INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of aztreonam for injection, USP and other antibacterial drugs, aztreonam for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Aztreonam for Injection is indicated for the treatment of the following infections caused by susceptible Gram-negative microorganisms: Urinary Tract Infections (complicated and uncomplicated), including pyelonephritis and cystitis (initial and recurrent) caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Enterobacter cloacae, Klebsiella oxytoca *, Citrobacter species*, and Serratia marcescens *. Lower Respiratory Tract Infections , including pneumonia and bronchitis caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Haemophilus influenzae, Proteus mirabilis, Enterobacter species, and Serratia marcescens *. Septicemia caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis *, Serratia marcescens *, and Enterobacter species. Skin and Skin-Structure Infections , including those associated with postoperative wounds, ulcers, and burns, caused by Escherichia coli, Proteus mirabilis, Serratia marcescens, Enterobacter species, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Citrobacter species*. *Efficacy for this organism in this organ system was studied in fewer than 10 infections. Intra-abdominal Infections , including peritonitis caused by Escherichia coli, Klebsiella species including K. pneumoniae, Enterobacter species including E. cloacae *, Pseudomonas aeruginosa, Citrobacter species* including C. freundii *, and Serratia species* including S. marcescens *. Gynecologic Infections , including endometritis and pelvic cellulitis caused by Escherichia coli, Klebsiella pneumoniae *, Enterobacter species* including E. cloacae *, and Proteus mirabilis *. Aztreonam for injection is indicated for adjunctive therapy to surgery in the management of infections caused by susceptible organisms, including abscesses, infections complicating hollow viscus perforations, cutaneous infections, and infections of serous surfaces. Aztreonam for injection is effective against most of the commonly encountered Gram-negative aerobic pathogens seen in general surgery. Concurrent Therapy Concurrent initial therapy with other antimicrobial agents and aztreonam for injection is recommended before the causative organism(s) is known in seriously ill patients who are also at risk of having an infection due to Gram-positive aerobic pathogens. If anaerobic organisms are also suspected as etiologic agents, therapy should be initiated using an anti-anaerobic agent concurrently with aztreonam for injection (see DOSAGE AND ADMINISTRATION ). Certain antibiotics (e.g., cefoxitin, imipenem) may induce high levels of beta-lactamase in vitro in some Gram-negative aerobes such as Enterobacter and Pseudomonas species, resulting in antagonism to many beta-lactam antibiotics including aztreonam. These in vitro findings suggest that such beta-lactamase-inducing antibiotics not be used concurrently with aztreonam. Following identification and susceptibility testing of the causative organism(s), appropriate antibiotic therapy should be continued.

DOSAGE AND ADMINISTRATION Dosage in Adult Patients Aztreonam for injection may be administered intravenously or by intramuscular injection. Dosage and route of administration should be determined by susceptibility of the causative organisms, severity and site of infection, and the condition of the patient. Table 2: Aztreonam for Injection Dosage Guidelines for Adults* * Maximum recommended dose is 8 g per day. Type of Infection Dose Frequency (hours) Urinary tract infections 500 mg or 1 g 8 or 12 Moderately severe systemic infections 1 g or 2 g 8 or 12 Severe systemic or life-threatening infections 2 g 6 or 8 Because of the serious nature of infections due to Pseudomonas aeruginosa , dosage of 2 g every six or eight hours is recommended, at least upon initiation of therapy, in systemic infections caused by this organism. The intravenous route is recommended for patients requiring single doses greater than 1 g or those with bacterial septicemia, localized parenchymal abscess (e.g., intra-abdominal abscess), peritonitis, or other severe systemic or life-threatening infections. The duration of therapy depends on the severity of infection. Generally, aztreonam for injection should be continued for at least 48 hours after the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. Persistent infections may require treatment for several weeks. Doses smaller than those indicated should not be used. Renal Impairment in Adult Patients Prolonged serum levels of aztreonam may occur in patients with transient or persistent renal insufficiency. Therefore, the dosage of aztreonam for injection should be halved in patients with estimated creatinine clearances between 10 and 30 mL/min/1.73 m 2 after an initial loading dose of 1 or 2 g. When only the serum creatinine concentration is available, the following formula (based on sex, weight, and age of the patient) may be used to approximate the creatinine clearance (Clcr). The serum creatinine should represent a steady state of renal function. Males: Clcr = weight (kg) x (140 - age) 72 x serum creatinine (mg/dL) Females: 0.85 x above value In patients with severe renal failure (creatinine clearance less than 10 mL/min/1.73 m 2 ), such as those supported by hemodialysis, the usual dose of 500 mg, 1 g, or 2 g should be given initially. The maintenance dose should be one-fourth of the usual initial dose given at the usual fixed interval of 6, 8, or 12 hours. For serious or life-threatening infections, in addition to the maintenance doses, one-eighth of the initial dose should be given after each hemodialysis session. Dosage in the Elderly Renal status is a major determinant of dosage in the elderly; these patients in particular may have diminished renal function. Serum creatinine may not be an accurate determinant of renal status. Therefore, as with all antibiotics eliminated by the kidneys, estimates of creatinine clearance should be obtained and appropriate dosage modifications made if necessary. Dosage in Pediatric Patients Aztreonam for injection should be administered intravenously to pediatric patients with normal renal function. There are insufficient data regarding intramuscular administration to pediatric patients or dosing in pediatric patients with renal impairment. (See PRECAUTIONS: Pediatric Use . ) Table 3: Aztreonam for Injection Dosage Guidelines for Pediatric Patients* * Maximum recommended dose is 120 mg/kg/day. Type of Infection Dose Frequency (hours) Mild to moderate infections 30 mg/kg 8 Moderate to severe infections 30 mg/kg 6 or 8

WARNINGS Both animal and human data suggest that aztreonam for injection, USP is rarely cross-reactive with other beta-lactam antibiotics and weakly immunogenic. Treatment with aztreonam can result in hypersensitivity reactions in patients with or without prior exposure. (See CONTRAINDICATIONS . ) Careful inquiry should be made to determine whether the patient has any history of hypersensitivity reactions to any allergens. While cross-reactivity of aztreonam with other beta-lactam antibiotics is rare, this drug should be administered with caution to any patient with a history of hypersensitivity to beta-lactams (e.g., penicillins, cephalosporins, and/or carbapenems). Treatment with aztreonam can result in hypersensitivity reactions in patients with or without prior exposure to aztreonam. If an allergic reaction to aztreonam occurs, discontinue the drug and institute supportive treatment as appropriate (e.g., maintenance of ventilation, pressor amines, antihistamines, corticosteroids). Serious hypersensitivity reactions may require epinephrine and other emergency measures. (See ADVERSE REACTIONS . ) Clostridium difficile- associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including aztreonam for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. Rare cases of toxic epidermal necrolysis have been reported in association with aztreonam in patients undergoing bone marrow transplant with multiple risk factors including sepsis, radiation therapy, and other concomitantly administered drugs associated with toxic epidermal necrolysis.

CONTRAINDICATIONS CAYSTON is contraindicated in patients with a known allergy to aztreonam. Contraindicated in patients with a known allergy to aztreonam. ( 4 )

CLINICAL PHARMACOLOGY Single 30-minute intravenous infusions of 500 mg, 1 g, and 2 g doses of AZACTAM in healthy subjects produced aztreonam peak serum levels of 54 mcg/mL, 90 mcg/mL, and 204 mcg/mL, respectively, immediately after administration; at 8 hours, serum levels were 1 mcg/mL, 3 mcg/mL, and 6 mcg/mL, respectively (Figure 1). Single 3-minute intravenous injections of the same doses resulted in serum levels of 58 mcg/mL, 125 mcg/mL, and 242 mcg/mL at 5 minutes following completion of injection. Serum concentrations of aztreonam in healthy subjects following completion of single intramuscular injections of 500 mg and 1 g doses are depicted in Figure 1; maximum serum concentrations occur at about 1 hour. After identical single intravenous or intramuscular doses of AZACTAM, the serum concentrations of aztreonam are comparable at 1 hour (1.5 hours from start of intravenous infusion) with similar slopes of serum concentrations thereafter. FIGURE 1 The serum levels of aztreonam following single 500 mg or 1 g (intramuscular or intravenous) or 2 g (intravenous) doses of AZACTAM exceed the MIC 90 for Neisseria sp., Haemophilus influenzae , and most genera of the Enterobacteriaceae for 8 hours (for Enterobacter sp., the 8-hour serum levels exceed the MIC for 80% of strains). For Pseudomonas aeruginosa , a single 2 g intravenous dose produces serum levels that exceed the MIC 90 for approximately 4 to 6 hours. All of the above doses of AZACTAM result in average urine levels of aztreonam that exceed the MIC 90 for the same pathogens for up to 12 hours. When aztreonam pharmacokinetics were assessed for adult and pediatric patients, they were found to be comparable (down to 9 months old). The serum half-life of aztreonam averaged 1.7 hours (1.5-2.0) in subjects with normal renal function, independent of the dose and route of administration. In healthy subjects, based on a 70 kg person, the serum clearance was 91 mL/min and renal clearance was 56 mL/min; the apparent mean volume of distribution at steady-state averaged 12.6 liters, approximately equivalent to extracellular fluid volume. In elderly patients, the mean serum half-life of aztreonam increased and the renal clearance decreased, consistent with the age-related decrease in creatinine clearance. The dosage of AZACTAM should be adjusted accordingly (see DOSAGE AND ADMINISTRATION: Renal Impairment in Adult Patients ). In patients with impaired renal function, the serum half-life of aztreonam is prolonged. (See DOSAGE AND ADMINISTRATION: Renal Impairment in Adult Patients .) The serum half-life of aztreonam is only slightly prolonged in patients with hepatic impairment since the liver is a minor pathway of excretion. Average urine concentrations of aztreonam were approximately 1100 mcg/mL, 3500 mcg/mL, and 6600 mcg/mL within the first 2 hours following single 500 mg, 1 g, and 2 g intravenous doses of AZACTAM (30-minute infusions), respectively. The range of average concentrations for aztreonam in the 8- to 12-hour urine specimens in these studies was 25 to 120 mcg/mL. After intramuscular injection of single 500 mg and 1 g doses of AZACTAM, urinary levels were approximately 500 mcg/mL and 1200 mcg/mL, respectively, within the first 2 hours, declining to 180 mcg/mL and 470 mcg/mL in the 6- to 8-hour specimens. In healthy subjects, aztreonam is excreted in the urine about equally by active tubular secretion and glomerular filtration. Approximately 60% to 70% of an intravenous or intramuscular dose was recovered in the urine by 8 hours. Urinary excretion of a single parenteral dose was essentially complete by 12 hours after injection. About 12% of a single intravenous radiolabeled dose was recovered in the feces. Unchanged aztreonam and the inactive beta-lactam ring hydrolysis product of aztreonam were present in feces and urine. Intravenous or intramuscular administration of a single 500 mg or 1 g dose of AZACTAM every 8 hours for 7 days to healthy subjects produced no apparent accumulation of aztreonam or modification of its disposition characteristics; serum protein binding averaged 56% and was independent of dose. An average of about 6% of a 1 g intramuscular dose was excreted as a microbiologically inactive open beta-lactam ring hydrolysis product (serum half-life approximately 26 hours) of aztreonam in the 0‑ to 8-hour urine collection on the last day of multiple dosing. Renal function was monitored in healthy subjects given aztreonam; standard tests (serum creatinine, creatinine clearance, BUN, urinalysis, and total urinary protein excretion) as well as special tests (excretion of N-acetyl-β-glucosaminidase, alanine aminopeptidase, and β 2 -microglobulin) were used. No abnormal results were obtained. Aztreonam achieves measurable concentrations in the following body fluids and tissues: Table 1: Extravascular Concentrations of Aztreonam After a Single Parenteral Dose a a Tissue penetration is regarded as essential to therapeutic efficacy, but specific tissue levels have not been correlated with specific therapeutic effects. Fluid or Tissue Dose (g) Route Hours Post-injection Number of Patients Mean Concentration (mcg/mL or mcg/g) Fluids bile 1 IV 2 10 39 blister fluid 1 IV 1 6 20 bronchial secretion 2 IV 4 7 5 cerebrospinal fluid (inflamed meninges) 2 IV 0.9-4.3 16 3 pericardial fluid 2 IV 1 6 33 pleural fluid 2 IV 1.1-3.0 3 51 synovial fluid 2 IV 0.8-1.9 11 83 Tissues atrial appendage 2 IV 0.9-1.6 12 22 endometrium 2 IV 0.7-1.9 4 9 fallopian tube 2 IV 0.7-1.9 8 12 fat 2 IV 1.3-2.0 10 5 femur 2 IV 1.0-2.1 15 16 gallbladder 2 IV 0.8-1.3 4 23 kidney 2 IV 2.4-5.6 5 67 large intestine 2 IV 0.8-1.9 9 12 liver 2 IV 0.9-2.0 6 47 lung 2 IV 1.2-2.1 6 22 myometrium 2 IV 0.7-1.9 9 11 ovary 2 IV 0.7-1.9 7 13 prostate 1 IM 0.8-3.0 8 8 skeletal muscle 2 IV 0.3-0.7 6 16 skin 2 IV 0.0-1.0 8 25 sternum 2 IV 1 6 6 The concentration of aztreonam in saliva at 30 minutes after a single 1 g intravenous dose (9 patients) was 0.2 mcg/mL; in human milk at 2 hours after a single 1 g intravenous dose (6 patients), 0.2 mcg/mL, and at 6 hours after a single 1 g intramuscular dose (6 patients), 0.3 mcg/mL; in amniotic fluid at 6 to 8 hours after a single 1 g intravenous dose (5 patients), 2 mcg/mL. The concentration of aztreonam in peritoneal fluid obtained 1 to 6 hours after multiple 2 g intravenous doses ranged between 12 mcg/mL and 90 mcg/mL in 7 of 8 patients studied. Aztreonam given intravenously rapidly reaches therapeutic concentrations in peritoneal dialysis fluid; conversely, aztreonam given intraperitoneally in dialysis fluid rapidly produces therapeutic serum levels. Concomitant administration of probenecid or furosemide and aztreonam causes clinically insignificant increases in the serum levels of aztreonam. Single-dose intravenous pharmacokinetic studies have not shown any significant interaction between aztreonam and concomitantly administered gentamicin, nafcillin sodium, cephradine, clindamycin, or metronidazole. No reports of disulfiram-like reactions with alcohol ingestion have been noted; this is not unexpected since aztreonam does not contain a methyl-tetrazole side chain. Microbiology Mechanism of Action Aztreonam is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Aztreonam has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria. Mechanism of Resistance Resistance to aztreonam is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability. Interaction with Other Antimicrobials Aztreonam and aminoglycosides have been shown to be synergistic in vitro against most strains of P. aeruginosa , many strains of Enterobacteriaceae, and other Gram-negative aerobic bacilli. Aztreonam has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND U