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    Cephalosporin and Beta-Lactamase Inhibitor Combination Antibiotics

    DEA CLASS

    Rx

    DESCRIPTION

    Combination intravenous anti-infective, including a third generation cephalosporin and beta-lactamase inhibitor
    For complicated intra-abdominal infections (with metronidazole) and complicated urinary tract infections in adults
    Decreased efficacy seen in patients with baseline CrCl 30—50 mL/min during clinical trials; monitor SCr daily and adjust the dose as needed

    COMMON BRAND NAMES

    AVYCAZ

    HOW SUPPLIED

    AVYCAZ Intravenous Inj Pwd F/Sol: 2-0.5g

    DOSAGE & INDICATIONS

    For the treatment of complicated urinary tract infection (UTI), including pyelonephritis, caused by susceptible bacteria.
    Intravenous dosage
    Adults

    2.5 g (2 g ceftazidime and 0.5 g avibactam) IV every 8 hours for 7 to 14 days.

    For the treatment of complicated intraabdominal infections when administered in combination with metronidazole.
    Intravenous dosage
    Adults

    2.5 g (2 g ceftazidime and 0.5 g avibactam) IV every 8 hours in combination with metronidazole for 5 to 14 days.

    For the treatment of sepsis†.
    Intravenous dosage
    Adults

    2.5 g (2 g ceftazidime and 0.5 g avibactam) IV every 8 hours is used for other indications. Start within 1 hour of recognition as part of empiric multi-drug therapy. Duration of therapy is generally 7 to 10 days, but may be shorter or longer depending upon patient response, site of infection, and pathogen(s) isolated. Treatment may be narrowed with pathogen identification and/or adequate clinical response.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    7.5 g/day (6 g/day ceftazidime and 1.5 g/day avibactam) IV.

    Geriatric

    7.5 g/day (6 g/day ceftazidime and 1.5 g/day avibactam) IV.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are needed.

    Renal Impairment

    CrCl more than 50 mL/minute: no dosage adjustment needed.
    CrCl 31 to 50 mL/minute: 1.25 g (1 g ceftazidime and 0.25 g avibactam) IV every 8 hours.
    CrCl 16 to 30 mL/minute: 0.94 g (0.75 g ceftazidime and 0.19 g avibactam) IV every 12 hours.
    CrCl 6 to 15 mL/minute: 0.94 g (0.75 g ceftazidime and 0.19 g avibactam) IV every 24 hours.
    CrCl 5 mL/minute or less: 0.94 g (0.75 g ceftazidime and 0.19 g avibactam) IV every 48 hours.
     
    Intermittent hemodialysis
    Administer the dose and frequency based on patients estimated creatinine clearance, as shown above. Both ceftazidime and avibactam are removed by hemodialysis; therefore, administer the dose after hemodialysis on hemodialysis days.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration whenever solution and container permit. The diluted solution ranges from clear to light yellow.
    Each vial contains 2.5 g ceftazidime; avibactam (2 g ceftazidime and 0.5 g avibactam).

    Intravenous Administration

    Reconstitution:
    Using aseptic technique, reconstitute the dry powder with 10 mL of one of the following solutions: Sterile Water for Injection, Lactated Ringer's Injection , 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or any combination of dextrose and sodium chloride that contains up to 2.5% Dextrose Injection and 0.45% Sodium Chloride Injection.
    Ensure the dry powder is dissolve by gently mixing.
    The constituted solution will have an approximate ceftazidime concentration of 0.167 g/mL and an approximate avibactam concentration of 0.042 g/mL with an approximate final volume of 12 mL.
    The constituted solution is NOT for direct injection and MUST be diluted before intravenous infusion.
    Storage: The solution should be further diluted within 30 minutes of reconstitution.
     
    Dilution:
    Prepare the required dose for infusion by withdrawing the appropriate volume from the reconstituted vial.
    For a 2.5 g dose (2 g ceftazidime and 0.5 g avibactam), withdraw 12 mL (entire contents) of the reconstituted solution for further dilution.
    For a 1.25 g dose (1 g ceftazidime and 0.25 g avibactam), withdraw 6 mL of the reconstituted solution for further dilution.
    For a 0.94 g dose (0.75 g ceftazidime and 0.19 g avibactam), withdraw 4.5 mL of the reconstituted solution for further dilution.
    Using the same solution that was selected for reconstitution, dilute to a total volume of 50—250 mL. If Sterile Water for Injection was used for reconstitution, use any other appropriate diluent for dilution.
    Gently mix.
    Final concentrations for 50 mL volume: 40 mg/mL ceftazidime and 10 mg/mL avibactam.
    Final concentrations for 250 mL volume: 8 mg/mL ceftazidime and 2 mg/mL avibactam.
    Storage: Administer diluted solution within 12 hours if stored at room temperature of 25 degrees C (77 degrees F). Diluted solution may be stored for up to 24 hours under refrigeration at 2—8 degrees C (36—46 degrees F), with subsequent storage for up to 12 hours at room temperature.
     
    Intermittent IV infusion:
    Administer via intravenous infusion over 2 hours.

    STORAGE

    AVYCAZ:
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store in carton until time of use
    - Store unreconstituted product at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    A false-positive reaction for glucose in the urine has been observed in patients receiving cephalosporins, such as ceftazidime; avibactam, and using Benedict's solution, Fehling's solution, or Clinitest tablets for urine glucose testing. However, this reaction has not been observed with glucose oxidase tests (e.g., Tes-tape, Clinistix, Diastix). Patients with diabetes mellitus who test their urine for glucose should use glucose tests based on enzymatic glucose oxidase reactions while on ceftazidime; avibactam treatment.
     
    A positive direct Coombs test may develop in some patients. In hematologic studies or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs test of newborns whose mothers received ceftazidime; avibactam before delivery, clinicians should keep in mind that a positive Coombs test may be due to the drug.

    Carbapenem hypersensitivity, cephalosporin hypersensitivity, penicillin hypersensitivity, serious rash

    Ceftazidime, avibactam is contraindicated for use in patients with a cephalosporin hypersensitivity or cephamycin hypersensitivity. Prior to initiating treatment, question patients regarding penicillin hypersensitivity and/or carbapenem hypersensitivity. The structural similarity between ceftazidime and other beta-lactam antibiotics means that cross-reactivity can occur. Beta-lactams can cause a variety of hypersensitivity reactions ranging from mild rash to fatal anaphylaxis. Patients who have previously experienced a severe beta-lactam hypersensitivity, such as a serious rash, should not receive ceftazidime; avibactam. If an allergic reaction develops during treatment, discontinue use of ceftazidime; avibactam.

    Colitis, diarrhea, GI disease, inflammatory bowel disease, pseudomembranous colitis, ulcerative colitis

    Almost all antibacterial agents, including ceftazidime; avibactam, have been associated with pseudomembranous colitis (antibiotic-associated colitis) which may range in severity from mild to life-threatening. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea following antibacterial administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. Following diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over 2 months or more following discontinuation of systemic antibiotic therapy; a careful medical history should be taken.

    Coma, encephalopathy, renal failure, renal impairment, seizures

    Use caution when administering ceftazidime; avibactam to patients with renal impairment or renal failure since both drug components are eliminated via renal mechanisms. In a clinical study in patients with complicated intraabdominal infections, cure rates were lower in patients with an estimated creatinine clearance (CrCl) of 30 to 50 mL/minute when compared to those with normal renal function; however, it should be noted that doses used in this study were 33% lower than currently recommended. In order to ensure accurate dosing, monitor CrCl at least daily in those patients with changing renal function, particularly early during treatment. For patients with a CrCl < 50 mL/minute, dosage and dose frequency must be adjusted. Administration of an unadjusted dose in patients with impaired renal function may result in elevated ceftazidime serum concentrations. Elevated concentrations of ceftazidime have resulted in neurotoxicity, including seizures, encephalopathy, asterixis, coma, neuromuscular excitability, and myoclonia.

    Coagulopathy, vitamin K deficiency

    All cephalosporins may rarely cause hypothrombinemia and increase the risk of bleeding; however, those cephalosporins containing the MTT side chain (e.g., cefoperazone, cefamandole, cefotetan) have the greatest association with bleeding. Cephalosporins should be used cautiously in patients with a preexisting coagulopathy (e.g., vitamin K deficiency) since these individuals are at a higher risk for developing bleeding complications. Treatment with ceftazidime; avibactam may result in a false-positive direct Coombs' tests; in clinical studies, no cases of hemolytic anemia were reported.

    Pregnancy

    No adequate or well-controlled studies with ceftazidime; avibactam have been conducted in pregnant women. Data from animal studies revealed no teratogenic effects in the off-spring of rats and rabbits given doses up to 40-times the recommended human dose. Because animal studies are not always predictive of human response, ceftazidime; avibactam should be used during pregnancy only if clearly needed.

    Breast-feeding

    Use caution if administering ceftazidime; avibactam to breast-feeding mothers, as small quantities of ceftazidime are excreted in human breast milk; the presence of avibactam in human milk is unknown. Although considered unlikely, exposure of infants to ceftazidime through breast-feeding may alter gut flora and result in diarrhea or related complications (e.g., dehydration). Because the risk of serious reactions is relatively rare, the use of many cephalosporins is considered compatible with breast feeding. Previous American Academy of Pediatrics recommendations considered ceftazidime as generally compatible with breast-feeding.

    ADVERSE REACTIONS

    Severe

    renal failure (unspecified) / Delayed / 0-1.0
    seizures / Delayed / Incidence not known
    coma / Early / Incidence not known

    Moderate

    constipation / Delayed / 2.0-2.0
    elevated hepatic enzymes / Delayed / 0-1.0
    hypokalemia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    nephrolithiasis / Delayed / 0-1.0
    candidiasis / Delayed / 0-1.0
    phlebitis / Rapid / 0-1.0
    myoclonia / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known
    superinfection / Delayed / Incidence not known
    pseudomembranous colitis / Delayed / Incidence not known

    Mild

    diarrhea / Early / 3.0-8.0
    nausea / Early / 3.0-7.0
    vomiting / Early / 5.0-5.0
    headache / Early / 3.0-3.0
    dizziness / Early / 2.0-2.0
    abdominal pain / Early / 1.0-1.0
    dysgeusia / Early / 0-1.0
    anxiety / Delayed / 0-1.0
    maculopapular rash / Early / 0-1.0
    urticaria / Rapid / 0-1.0
    pruritus / Rapid / 0-1.0
    rash (unspecified) / Early / 0-1.0
    asterixis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Amikacin: (Minor) Ceftazidime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Aminoglycosides: (Minor) Ceftazidime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Bumetanide: (Minor) Ceftazidime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Ethacrynic Acid: (Minor) Ceftazidime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Furosemide: (Minor) Ceftazidime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Gentamicin: (Minor) Ceftazidime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Kanamycin: (Minor) Ceftazidime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Loop diuretics: (Minor) Ceftazidime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Paromomycin: (Minor) Ceftazidime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Probenecid: (Major) Avoid concurrent administration of ceftazidime; avibactam with probenicid. Use of these medications together may decrease the renal clearance of avibactam; thereby resulting in prolonged drug exposures. Avibactam is a substrate of the renal organic anion transporters (OAT)1 and OAT3; probenecid is a potent inhibitor of these transporters. An in vitro study found probencid blocked 56% to 70% of avibactam uptake by these transporters.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
    Streptomycin: (Minor) Ceftazidime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Tobramycin: (Minor) Ceftazidime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Torsemide: (Minor) Ceftazidime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Warfarin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.

    PREGNANCY AND LACTATION

    Pregnancy

    No adequate or well-controlled studies with ceftazidime; avibactam have been conducted in pregnant women. Data from animal studies revealed no teratogenic effects in the off-spring of rats and rabbits given doses up to 40-times the recommended human dose. Because animal studies are not always predictive of human response, ceftazidime; avibactam should be used during pregnancy only if clearly needed.

    Use caution if administering ceftazidime; avibactam to breast-feeding mothers, as small quantities of ceftazidime are excreted in human breast milk; the presence of avibactam in human milk is unknown. Although considered unlikely, exposure of infants to ceftazidime through breast-feeding may alter gut flora and result in diarrhea or related complications (e.g., dehydration). Because the risk of serious reactions is relatively rare, the use of many cephalosporins is considered compatible with breast feeding. Previous American Academy of Pediatrics recommendations considered ceftazidime as generally compatible with breast-feeding.

    MECHANISM OF ACTION

    Ceftazidime, like all beta-lactam antibiotics, is mainly bactericidal and displays time-dependant killing (i.e., antibacterial activity occurs when drug concentrations at the infection site are higher then the minimum inhibitory concentration of the bacteria). Ceftazidime inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. Penicillin-binding proteins are responsible for several steps in the synthesis of the cell wall. Penicillin-binding proteins vary among different bacterial species; thus, the intrinsic activity of ceftazidime against a particular microorganism depends on its ability to gain access to and bind with the necessary PBP. Resistance occurs as a result of decreased permeability, alterations of PBPs, and hydrolysis by beta-lactamases.
     
    In particular, ceftazidime preferentially binds to PBP-3 of gram-negative rods. Since PBP-3 is responsible for formation of the septum during cell division, ceftazidime's inhibition of these proteins causes elongation of the bacteria, inhibition of bacterial cell division, and breakage of the cell wall resulting in cell lysis and death. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor.
     
    Due to the presence of an aminothiazolyl side chain, third generation cephalosporins displays enhanced activity against gram-negative bacteria, particularly the Enterobacteriaceae. In addition, because ceftazidime also contains a 2-carboxy-2-oxypropane imino group, it shows increased activity against Pseudomonas aeruginosa, which gives it an important advantage over other cephalosporins. However, the presence of the 2-carboxy-2-oxypropane imino group limits ceftazidimes activity against most gram-positive bacteria. In addition, ceftazidime is inactive against the anaerobes Bacteroides fragilis and Clostridium sp.
     
    Avibactam (like tazobactam, sulbactam and clavulanic acid) is an inhibitor of bacterial beta-lactamases. Avibactam protects ceftazidime against the following beta-lactamases: TEM, SHV, CTX-M, Klebsiella pneumonia carbapenemase (KPC), AmpC, and certain oxacillinases (OXA). Avibactam will not protect ceftazidime against metallo-beta lactamase producing bacteria, nor bacteria that overexpress efflux pumps or have porin mutations.

    PHARMACOKINETICS

    Ceftazidime; avibactam is administered intravenously.
    Ceftazidime: Approximately 10% of the circulating drug is protein-bound. Ceftazidime is distributed into most body tissues and fluids. Average tissue or fluid ceftazidime concentrations after a 2 g IV dose include bile (36.4 mcg/mL), synovial fluid (25.6 mcg/mL), peritoneal fluid (48.6 mcg/mL), sputum (9 mcg/mL), CSF (9.8 mcg/mL), CSF with inflamed meninges (9.4 mcg/mL), aqueous humor (11 mcg/mL), blister fluid (19.7 mcg/mL), lymphatic fluid (23.4 mcg/mL), bone (31.1 mcg/mL), heart muscle (12.7 mcg/mL), skin (6.6 mcg/mL), skeletal muscle (9.4 mcg/mL), and myometrium (18.7 mcg/mL). Up to 90% of an administered dose is excreted unchanged into the urine over a 24 hour period, primarily via glomerular filtration; urine concentrations average 2100 mcg/mL after a 500 mg IM dose and 12,000 mcg/mL after a 2 g IV dose. Mean renal clearance is about 100 mL/min. In patients with normal renal function, the elimination half-life of ceftazidime is 1.5—2 hours, but half-life increases as renal function declines.
    Avibactam: At steady state, avibactam has a volume of distribution of 22 L, with 5—8% of the circulating drug being bound to human plasma protein. The drug does not appear to undergo hepatic metabolism; however, it is a substrate for renal organic anion transporters (OAT)1 and OAT3. These transporters may contribute to elimination of the drug by actively removing it from the blood compartment. Excretion occur primarily in the kidneys, with 85% of a dose recovered as unchanged drug within 96 hours. Renal clearance is 158 mL/min, suggesting active tubular secretion contributes to the excretion of avibactam. In patients with normal renal function, the elimination half-life is 2 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: OAT1 and OAT3
    Avibactam is a substrate of OAT1 and OAT3. Inhibitors of these transporters may decrease renal clearance of avibactam, resulting in prolonged drug exposure.

    Intravenous Route

    Ceftazidime: The maximum serum concentration (Cmax) and drug exposure (AUC) of ceftazidime increase in a dose proportional manner. Drug accumulation has not been observed following repeated IV infusions every 8 hours for up to 11 days.
    Avibactam: Over a dose range of 50 mg to 2000 mg, avibactam demonstrate approximately linear pharmacokinetics. Drug accumulation has not been observed following repeated IV infusions every 8 hours for up to 11 days.