Ceftazidime

Ceftazidime is a semisynthetic, third generation cephalosporin antibiotic.

Uses

Ceftazidime is used for the treatment of bone and joint infections, intra-abdominal and gynecologic infections, meningitis and other CNS infections, lower respiratory tract infections, skin and skin structure infections, and complicated or uncomplicated urinary tract infections caused by susceptible bacteria.

The drug also is used for empiric anti-infective agent therapy in febrile neutropenic patients and has been used for perioperative prophylaxis. Ceftazidime therapy may be started pending results of susceptibility tests, but should be discontinued if the organism is found to be resistant to the drug.

When the causative organism is unknown, concomitant therapy with another anti-infective agent may be indicated pending results of in vitro susceptibility tests. In severe or life-threatening infections or in immunocompromised patients, ceftazidime may be used concomitantly with other anti-infectives such as aminoglycosides, vancomycin, or clindamycin.

Gram-positive Aerobic Bacterial Infections

Like other parenteral third generation cephalosporins (cefoperazone, cefotaxime, ceftizoxime, ceftriaxone), ceftazidime is less active than first and second generation cephalosporins against some gram-positive bacteria (e.g., staphylococci) and generally should not be used in the treatment of infections caused by these organisms when a penicillin or first or second generation cephalosporin could be used.

Although ceftazidime has been effective when used alone in adults or children for the treatment of septicemia, cellulitis, urinary tract infections,osteomyelitis, or respiratory tract infections (including pneumonia) caused by susceptible gram-positive cocci (e.g., Staphylococcus aureus, S. epidermidis, groups A and B streptococci, Streptococcus pneumoniae), treatment failures also have been reported in some of these infections, especially in immunocompromised patients or patients with cystic fibrosis. Therefore, some clinicians recommend that ceftazidime not be used alone for empiric therapy in infections where gram-positive bacteria may be involved (e.g., community-acquired pneumonia).

Gram-negative Aerobic Bacterial Infections

Ceftazidime generally has been effective when used alone in adults or children for the treatment of respiratory tract infections (including pneumonia), skin and skin structure infections,osteomyelitis, septicemia, intra-abdominal infections, or urinary tract infections caused by susceptible Enterobacteriaceae (e.g., Enterobacter, Escherichia coli, Klebsiella, Morganella, Proteus, Serratia).

A principal use of ceftazidime is for the treatment of infections known or suspected to be caused by multidrug-resistant Enterobacteriaceae (e.g., nosocomial urinary tract infections or pneumonia, suspected septicemia in non-neutropenic patients) and serious gram-negative infections when other anti-infectives are contraindicated or ineffective. It has been suggested that certain parenteral cephalosporins (i.e., cefepime, cefotaxime, ceftizoxime, ceftriaxone, ceftazidime) may be drugs of choice for the treatment of infections caused by susceptible strains of E. coli, K. pneumoniae, P. rettgeri, M. morganii, P. vulgaris, P. stuartii, or Serratia; an aminoglycoside should be used concomitantly in severe infections. There is some evidence that for the treatment of some infections (e.g., pneumonia, bacteremia) caused by susceptible Enterobacteriaceae, ceftazidime used alone can be as effective as a 2-drug regimen of a third generation cephalosporin or an extended-spectrum penicillin used in conjunction with an aminoglycoside.

Mixed Aerobic-Anaerobic Bacterial Infections

Ceftazidime has been used with some success in the treatment of mixed aerobic-anaerobic bacterial infections. The manufacturers indicate that ceftazidime may be used in the treatment of polymicrobial intra-abdominal infections caused by aerobic and anaerobic bacteria, including Bacteroides; however, the drug should not be used alone for the treatment of any infection when B. fragilis may be present, since it generally is inactive against this organism.

Meningitis and Other CNS Infections

Ceftazidime used in conjunction with an aminoglycoside is considered a regimen of choice for the treatment of meningitis caused by susceptible Pseudomonas aeruginosa or susceptible Enterobacteriaceae (e.g., E. coli, P. mirabilis, Enterobacter, S. marcescens). While ceftazidime also has been effective when used alone for the treatment of meningitis caused by susceptible Haemophilus influenzae, Neisseria meningitidis, or S. pneumoniae, cefotaxime or ceftriaxone generally is preferred when a cephalosporin is indicated for the treatment of meningitis caused by these organisms. (See Uses: Meningitis and Other CNS Infections in the Cephalosporins General Statement 8:12.06.)

Because preterm, low-birthweight neonates are at increased risk for nosocomial infection caused by staphylococci or gram-negative bacilli, some clinicians suggest that these neonates receive an empiric regimen of IV ceftazidime and IV vancomycin for suspected bacterial meningitis. Immunocompromised individuals, geriatric individuals, and individuals with recent head trauma, neurosurgery, or CSF shunts also are at increased risk for meningitis caused by gram-negative bacilli and some clinicians recommend that IV ceftazidime be use for empiric therapy in these patients.

If ceftazidime is used for empiric therapy in individuals with meningitis, concomitant use of IV ampicillin should be considered to provide coverage against Listeria monocytogenes, especially in patients who are immunocompromised, infants younger than 3 months of age, or adults older than 50 years of age. In addition, for empiric therapy of meningitis in individuals with recent head trauma, neurosurgery, or CSF shunts, concomitant use of vancomycin should be considered to provide coverage against gram-positive bacteria.

When results of culture and in vitro susceptibility tests become available and the pathogen is identified, the empiric anti-infective regimen should be modified (if necessary) to ensure that the most effective regimen is being administered. In patients with meningitis caused by Ps. aeruginosa, many clinicians recommend that therapy be initiated with a regimen of ceftazidime and a parenteral aminoglycoside. If the patient fails to respond to this regimen, concomitant use of intrathecal or intraventricular aminoglycoside therapy or use of an alternative parenteral anti-infective (e.g., aztreonam, meropenem, a quinolone) should be considered based on results of in vitro susceptibility tests.

Septicemia

Ceftazidime is used in adult and pediatric patients for the treatment of septicemia caused by S. aureus, S. pneumoniae, E. coli, H. influenzae, K. pneumoniae, or Ps. aeruginosa. The manufacturers and some clinicians suggest that ceftazidime may be used alone for the treatment of suspected or confirmed bacteremia caused by susceptible

Enterobacteriaceae;however, other clinicians recommend that an aminoglycoside be used concomitantly for the treatment of gram-negative bacteremia in seriously ill patients. The choice of anti-infective agent for the treatment of sepsis syndrome should be based on the probable source of infection, gram-stained smears of appropriate clinical specimens, the immune status of the patient, and current patterns of bacterial resistance within the hospital and local community.

Certain parenteral cephalosporins (i.e., cefepime, cefotaxime, ceftizoxime, ceftriaxone, ceftazidime) are good choices for the treatment of gram-negative sepsis. However, the fact that ceftazidime has less activity against gram-positive cocci and that most cephalosporins (except cefepime and ceftazidime) have limited activity against Ps. aeruginosa should be considered. For the initial treatment of life-threatening sepsis in adults (unless presence of anaerobic bacteria, methicillin-resistant staphylococci, or bacterial endocarditis is suspected), some clinicians suggest use of a parenteral cephalosporin (i.e., cefepime, cefotaxime, ceftriaxone) given in conjunction with an aminoglycoside (amikacin, gentamicin, tobramycin).

Urinary Tract Infections

Ceftazidime is used in adult and pediatric patients for the treatment of complicated and uncomplicated urinary tract infections caused by Enterobacter, E. coli, Klebsiella, M. morganii, P. mirabilis, P. vulgaris, or Ps. aeruginosa.

The most appropriate agent for the treatment of urinary tract infections should be selected based on the severity of the infection and results of culture and in vitro susceptibility testing. It has been suggested that certain parenteral cephalosporins (i.e., cefepime, cefotaxime, ceftizoxime, ceftriaxone, ceftazidime) may be drugs of choice for the treatment of infections caused by susceptible Enterobacteriaceae, including susceptible strains of E. coli, K. pneumoniae, P. rettgeri, M. morganii, P. vulgaris, P. stuartii, or Serratia; an aminoglycoside should be used concomitantly in severe infections.

However, ceftazidime, like other third generation cephalosporins, generally should not be used in the treatment of uncomplicated urinary tract infections when other anti-infectives with a narrower spectrum of activity could be used.

Pseudomonas aeruginosa Infections

Ceftazidime is used in adult and pediatric patients for the treatment of septicemia, osteomyelitis, respiratory tract, skin and skin structure, or urinary tract infections caused by susceptible Ps. aeruginosa. The drug also is used for the treatment of meningitis caused by Ps. aeruginosa(see Uses: Meningitis and Other CNS Infections) and has been used for the treatment of malignant otitis externa caused by Ps. aeruginosa (see Otitis Externa under Uses: Otitis, in the Cephalosporins General Statement 8:12.06).

Ceftazidime generally has been considered a drug of choice for the treatment of infections caused by Ps. aeruginosa since it is more active in vitro on a weight basis against the organism than most other currently available cephalosporins and is active against some strains resistant to many other cephalosporins, aminoglycosides, and extended-spectrum penicillins.

However, ceftazidime-resistant strains of Ps. aeruginosa can emerge during therapy with the drug, and superinfection with resistant strains has occurred. In severe infections, especially in immunocompromised patients, concomitant use of ceftazidime and an aminoglycoside (e.g., amikacin, gentamicin, tobramycin) is recommended.

Ceftazidime is used alone or in conjunction with an aminoglycoside for the treatment of acute exacerbations of bronchopulmonary Ps. aeruginosa infections in children and adults with cystic fibrosis and generally is considered a drug of choice for these infections. In cystic fibrosis patients with acute exacerbations of Ps. aeruginosa infection, there is some evidence that an empiric regimen of ceftazidime and an aminoglycoside may be more effective than ceftazidime monotherapy; however, ceftazidime monotherapy appears to be as effective or more effective than monotherapy with aztreonam, ciprofloxacin, or meropenem or combination therapy with ticarcillin and tobramycin.

Although anti-infective therapy in patients with cystic fibrosis may result in clinical improvement and Ps. aeruginosa may be temporarily cleared from the sputum, a bacteriologic cure is rarely obtained and should not be expected.

Continuous IV infusion of ceftazidime has been used effectively for the treatment of Ps. aeruginosa infections in some adult and pediatric cystic fibrosis patients, including patients who failed to respond to ceftazidime administered by intermittent IV injection or infusion. Because a ceftazidime dosing regimen that consists of an IV loading dose followed by continuous IV infusion may provide more consistent concentrations of the drug than an intermittent dosing regimen, it has been suggested that such a regimen theoretically would be more effective in suppressingPs. aeruginosa and possibly may decrease emergence of drug-resistant strains of the organism.

Ceftazidime has been administered on an outpatient basis for the treatment of acute exacerbations of Ps. aeruginosa infections in cystic fibrosis patients; such community-based parenteral therapy generally is used to complete a course of ceftazidime therapy initiated during hospitalization.

Burkholderia Infections

Burkholderia cepacia Infections

Ceftazidime has been used alone or in conjunction with an aminoglycoside for the treatment of septicemia or pulmonary infections caused by Burkholderia cepacia (formerly Ps. cepacia). Patients with cystic fibrosis often are colonized with B. cepacia (with or without Ps. aeruginosa colonization). In addition, B. cepacia has recently been recognized as a cause of nosocomial pneumonia or nosocomial bacteremia in immunocompromised patients (e.g., patients with malignancy) B. cepacia is an aerobic, nonfermentative gram-negative bacilli resistant to many anti-infective agents, and no anti-infective regimen has been identified that effectively eradicates the organism in colonized cystic fibrosis patients. The optimum regimen for the treatment of infections caused by B. cepacia has not been identified.

Some clinicians consider co-trimoxazole the drug of choice and ceftazidime, chloramphenicol, and imipenem alternative agents for the treatment of B. cepacia infections.

Ceftazidime monotherapy has been used effectively to treat nosocomial B. cepacia bacteremia in a limited number of patients with severe underlying disease (e.g., malignancy); many of these patients had indwelling central venous catheters or recent surgery that may have precipitated the infection.

Melioidosis

Ceftazidime is considered by many clinicians to be a drug of choice for the treatment of severe melioidosis, a potentially life-threatening disease caused by B. pseudomallei (formerly Ps. pseudomallei). B. pseudomallei is an aerobic, nonfermentative gram-negative bacilli resistant to many anti-infective agents.

Ceftazidime monotherapy (40 mg/kg or 2 g IV 3 times daily) has been effective for the treatment of severe septicemic or pulmonary melioidosis, and has been associated with a lower mortality rate than a 3-drug regimen of IV chloramphenicol, oral doxycycline, and oral co-trimoxazole.

Other drugs that have been recommended as alternative agents for the treatment of melioidosis include imipenem, meropenem, amoxicillin and clavulanate potassium, or a regimen of chloramphenicol, doxycycline, and co-trimoxazole. In an open, prospective study in adults with acute severe melioidosis randomized to receive an initial parenteral regimen of IV ceftazidime or IV imipenem followed by an oral maintenance regimen, the survival rate at 48 hours was similar with both drugs (20.8% of those receiving ceftazidime and 25% of those receiving imipenem died within the first 48 hours), and the choice of initial drug did not appear to influence the final outcome; however, a higher percentage of patients receiving ceftazidime were considered to be treatment failures after 48 hours and had to be switched to an alternative drug because of primary treatment failure. B. pseudomallei is difficult to eradicate, and relapse of melioidosis commonly occurs.

Therefore, anti-infective therapy usually is continued for 6 weeks to 6 months or, alternatively, a parenteral anti-infective (e.g., ceftazidime) is given for at least 1-2 weeks followed by an oral regimen (e.g., amoxicillin and clavulanate potassium alone, doxycycline alone, or chloramphenicol, doxycycline, and co-trimoxazole) given for at least 3-6 months. The fact that resistant strains of B. pseudomallei have developed during ceftazidime therapy should be considered.

Vibrio vulnificus Infections

Ceftazidime is considered by some clinicians to be a drug of choice for the treatment of infections caused by Vibrio vulnificus. V. vulnificus, a gram-negative aerobic bacteria that can cause potentially fatal septicemia, wound infections, or gastroenteritis, generally is transmitted through ingestion of contaminated raw or undercooked seafood (especially raw oysters) or through contamination of a wound with seawater or seafood drippings. V. vulnificus is naturally present in marine environments, thrives in warm ocean water, and frequently is isolated from oysters and other shellfish harvested from the Gulf of Mexico and from US coastal waters along the Pacific and Atlantic ocean.

Individuals with preexisting liver disease are at high risk for developing fatal septicemia following ingestion of seafood contaminated with V. vulnificus and debilitated or immunocompromised individuals (e.g., those with chronic renal impairment, cancer, diabetes mellitus, steroid-dependent asthma, chronic GI disease) or individuals with iron overload states (e.g., thalassemia and hemochromatosis) also are at increased risk for fatal infections.

The incubation period for V. vulnificus infection reportedly is 1-7 days and the duration of illness usually is 2-8 days. In immunocompromised individuals, fever, nausea, myalgia, and abdominal cramps may occur as soon as 24-48 hours after ingestion of seafood contaminated with V. vulnificus and sepsis and cutaneous bullae may be present within 36 hours of the onset of symptoms. Because the case fatality rate for V. vulnificus septicemia exceeds 50% in immunocompromised individuals or those with preexisting liver disease, these individuals should be informed about the health hazards of ingesting raw or undercooked seafood (especially oysters), the need to avoid contact with seawater during the warm months, and the importance of using protective clothing (e.g., gloves) when handling shellfish.

V. vulnificus infection should be considered in the differential diagnosis of fever of unknown etiology, and individuals who present with fever (especially when bullae, cellulitis, or wound infection is present) and who have preexisting liver disease or are immunocompromised should be questioned regarding a history of raw oyster ingestion or seawater contact. While optimum anti-infective therapy for the treatment of V. vulnificus infections has not been identified, use of a tetracycline or third generation cephalosporin (e.g., cefotaxime, ceftazidime) is recommended. Because the high fatality rate associated with V. vulnificus infections, anti-infective therapy should be initiated promptly if indicated.

Empiric Therapy in Febrile Neutropenic Patients

Ceftazidime has been effective when used alone or in conjunction with other anti-infectives for empiric anti-infective therapy of presumed bacterial infections in febrile granulocytopenic adults or children.

Results of several studies in febrile granulocytopenic patients indicate that ceftazidime used alone may be as effective as combination regimens that include ceftazidime and an aminoglycoside (e.g., amikacin, gentamicin, tobramycin) or combination regimens that include some other b-lactam antibiotic (e.g., cefepime, ceftriaxone, piperacillin) and an aminoglycoside for empiric therapy in these patients.

Results of a randomized study in adults indicate that ceftazidime monotherapy (2 g IV every 8 hours) is as effective as meropenem monotherapy (1 g IV every 8 hours) for empiric anti-infective therapy in febrile neutropenic patients; at the end of therapy, a satisfactory response was obtained in 49 or 46% of those receiving ceftazidime or meropenem, respectively.

Because gram-positive bacteria are being reported with increasing frequency in febrile granulocytopenic patients and because ceftazidime is less active against these organisms than many other cephalosporins and b-lactam antibiotics, some clinicians suggest that an anti-infective agent active against staphylococci (e.g., vancomycin) probably should be used concomitantly if ceftazidime is used for empiric therapy in these patients. Unlike ceftazidime, other anti-infectives used for empiric therapy (e.g., cefepime, imipenem, meropenem) have good activity against viridans streptococci and S. pneumoniae and there is some evidence that concomitant use of vancomycin is required less frequently with cefepime than with ceftazidime.

Successful treatment of infections in granulocytopenic patients requires prompt initiation of empiric anti-infective therapy (even when fever is the only sign or symptom of infection) and appropriate modification of the initial regimen if the duration of fever and neutropenia is protracted, if a specific site of infection is identified, or if organisms resistant to the initial regimen are present.

The initial empiric regimen should be chosen based on the underlying disease and other host factors that may affect the degree of risk and on local epidemiologic data regarding usual pathogens in these patients and data regarding the type, frequency of occurrence, and in vitro susceptibility of bacterial isolates recovered from other patients in the same health-care facility.

The fact that gram-positive bacteria have become a predominant pathogen in febrile neutropenic patients should be considered when selecting an empiric anti-infective regimen. Gram-positive bacteria reportedly account for about 60-70% of microbiologically documented infections, although the rate of gram-negative infections is increasing in some health-care facilities. No empiric regimen has been identified that would be appropriate for initial treatment of all febrile neutropenic patients.

Regimens that have been recommended for empiric therapy in febrile neutropenic patients with presumed bacterial infections include monotherapy with a third or fourth generation cephalosporin (i.e., ceftazidime, cefepime) or a carbapenem (e.g., imipenem, meropenem); combination therapy consisting of a b-lactam antibiotic (e.g., ceftazidime, ceftriaxone), a carbapenem (e.g., imipenem, meropenem), an extended-spectrum penicillin (e.g., mezlocillin, piperacillin, ticarcillin), or a fixed combination of an extended-spectrum penicillin and a b-lactamase inhibitor (e.g., piperacillin sodium and tazobactam sodium, ticarcillin disodium and clavulanate potassium) given in conjunction with an aminoglycoside (e.g., amikacin, gentamicin, tobramycin); or combination therapy consisting of 2 b-lactam antibiotics (e.g., ceftazidime given with piperacillin).

The Infectious Diseases Society of America (IDSA) recommends use of a parenteral empiric regimen in most febrile neutropenic patients; use of an oral regimen (e.g., oral ciprofloxacin and oral amoxicillin and clavulanate) should only be considered in selected adults at low risk for complications who have no focus of bacterial infection and no signs or symptoms of systemic infection other than fever. At health-care facilities where gram-positive bacteria are common causes of serious infection and use of vancomycin in the initial empiric regimen is considered necessary, the IDSA recommends 2- or 3-drug combination therapy that includes vancomycin and either cefepime, ceftazidime, imipenem, or meropenem given with or without an aminoglycoside; vancomycin should be discontinued 24-48 hours later if a susceptible gram-positive bacterial infection is not identified.

At health-care facilities where vancomycin is not indicated in the initial empiric regimen, the IDSA recommends monotherapy with a third or fourth generation cephalosporin (ceftazidime, cefepime) or a carbapenem (imipenem, meropenem) for uncomplicated cases; however, for complicated cases or if anti-infective resistance is a problem, combination therapy consisting of an aminoglycoside (amikacin, gentamicin, tobramycin) given in conjunction with an antipseudomonal penicillin (ticarcillin and clavulanate, piperacillin and tazobactam), an antipseudomonal cephalosporin (cefepime, ceftazidime), or a carbapenem (imipenem, meropenem) is recommended.

Regardless of the initial regimen selected, patients should be reassessed after 3-5 days of treatment and the anti-infective regimen altered (if indicated) based on the presence or absence of fever, identification of the causative organism, and the clinical condition of the patient.

Published protocols for the treatment of infections in febrile neutropenic patients should be consulted for specific recommendations regarding selection of the initial empiric regimen, when to change the initial regimen, possible subsequent regimens, and duration of therapy in these patients. In addition, consultation with an infectious disease expert knowledgeable about infections in immunocompromised patients is advised.

Perioperative Prophylaxis

Ceftazidime has been effective when used for perioperative prophylaxis in patients undergoing vaginal hysterectomy, intra-abdominal surgery, or transurethral resection of the prostate; however, many clinicians and at least one manufacturer state that ceftazidime should not be used prophylactically. Other anti-infectives (e.g., cefazolin, cefotetan, cefoxitin) usually are the preferred drugs for perioperative prophylaxis. Some clinicians state that third generation cephalosporins (e.g., cefoperazone, cefotaxime, ceftriaxone, ceftazidime, ceftizoxime) and fourth generation cephalosporins (e.g., cefepime) should not be used for perioperative prophylaxis since they are expensive, some are less active than cefazolin against staphylococci, they have a spectrum of activity that is wider than necessary for organisms encountered in elective surgery, and their use for prophylaxis promotes emergence of resistant organisms.

Dosage and Administration

Reconstitution and Administration

Ceftazidime and ceftazidime sodium are administered by intermittent IV injection or infusion or by deep IM injection. Ceftazidime also has been administered by continuous IV infusion. Ceftazidime sodium has been administered intraperitoneally in dialysis solutions; it is not known whether ceftazidime (Ceptaz®) can be safely incorporated into dialysis fluid. The drug should not be administered by intra-arterial injection since arteriospasm and necrosis can occur.

Ceftazidime and ceftazidime sodium should be given IV rather than IM in patients with septicemia, meningitis, peritonitis, or other severe or life-threatening infections and in patients with lowered resistance resulting from malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or impending. If an aminoglycoside or vancomycin is administered concomitantly with ceftazidime or ceftazidime sodium, the drugs should be administered at separate sites.

Reconstituted and diluted solutions of ceftazidime or ceftazidime sodium should be inspected visually for particulate matter prior to administration whenever solution and container permit.

Intermittent IV Infusion

For intermittent IV infusion of a sodium carbonate formulation of ceftazidime, piggyback units of Fortaz®, Tazicef®, or Tazidime® containing 1 or 2 g of ceftazidime should be reconstituted with 100 mL of sterile water for injection or a compatible IV solution to provide a solution containing 10 or 20 mg/mL, respectively; reconstitution of the 1- or 2-g piggyback units of Tazidime® with 50 mL of sterile water for injection or other compatible IV fluid provides a solution containing 20 or 40 mg/mL, respectively. When reconstituting sodium carbonate formulations of ceftazidime, the diluent should be added in 2 stages. First, 10 mL of the diluent is injected into the piggyback unit and the unit shaken well to dissolve the drug.

With sodium carbonate formulations of ceftazidime, carbon dioxide is released as ceftazidime dissolves, generating pressure within the container; the solution will become clear within 1-2 minutes. A vent needle should then be inserted into the piggyback unit to release the pressure; to preserve sterility, it is important that the vent needle be inserted through the vial closure only after the drug has dissolved. The remaining volume of diluent should then be added.

The vent needle should be removed after the diluent has been added; however, additional pressure that may develop in the unit (especially after storage) should be relieved prior to administration of the drug. Alternatively, the contents of vials of Fortaz®, Tazicef®, or Tazidime® labeled as containing 500 mg, 1 g, or 2 g of ceftazidime should be reconstituted with 5, 10, or 10 mL, respectively, of sterile water for injection or a compatible IV solution to provide solutions containing approximately 100, 95-100, or 170-180 mg/mL, respectively; vials of Tazidime® labeled as containing 1 g of ceftazidime that are reconstituted with 5 mL of one of these diluents contain approximately 180 mg/mL.

After adding the diluent to the vial, the vial should be shaken to dissolve the drug. With sodium carbonate formulations of ceftazidime, carbon dioxide is released as the drug dissolves and the solution will become clear within 1-2 minutes.

The appropriate dose of the drug should then be added to a compatible IV solution. When withdrawing a dose from reconstituted vials of ceftazidime sodium, ensure that the syringe needle opening remains within the solution.

The withdrawn solution may contain some carbon dioxide bubbles which should be expelled from the syringe before injection. For intermittent IV infusion of the arginine formulation of ceftazidime, piggyback units of Ceptaz® containing 1 or 2 g of ceftazidime should be reconstituted with 100 mL of sterile water for injection or other compatible IV solution to provide a solution containing 10 or 20 mg/mL, respectively.

The arginine formulation of Ceptaz® dissolves without the evolution of gas; vials of Ceptaz® as supplied are under a slightly reduced pressure. Venting of Ceptaz® vials is not required during reconstitution, except with the piggyback (infusion pack) units during the latter stages of diluent addition. However, to preserve sterility, a vent needle should not be used until positive pressure has been generated in the container.

When the contents of the vial are dissolved, vials of Ceptaz® other than the piggyback units may still be under reduced pressure; this reduced pressure may be particularly noticeable with the 10-g pharmacy bulk package. Alternatively, the contents of vials of Ceptaz® labeled as containing 1 or 2 g of ceftazidime should be reconstituted with 10 mL of sterile water for injection or other compatible IV solution to provide solutions containing approximately 90-95 or 170-180 mg/mL, respectively.

The appropriate dose of the drug should then be added to a compatible IV solution. ADD-Vantage® vials labeled as containing 1 or 2 g of ceftazidime and pharmacy bulk packages of the arginine or sodium carbonate formulations of the drug should be reconstituted according to the manufacturer’s directions. Carbon dioxide that forms inside the package in sodium carbonate formulations of ceftazidime should be relieved by inserting a vent needle; to preserve sterility, it is important that the vent needle be inserted through the vial closure only after the drug has dissolved. The vent needle should be removed prior to use of the solution.

The contents of ceftazidime pharmacy bulk packages are not intended for direct IV infusion; doses of the drug from the reconstituted bulk packages must be further diluted in a compatible IV infusion solution prior to administration. Thawed solutions of the commercially available frozen ceftazidime sodium injection in dextrose may be administered by continuous or intermittent IV infusion.

The commercially available frozen ceftazidime sodium in dextrose injections should not be thawed by warming them in a water bath or by exposure to microwave radiation. A precipitate may form while the commercially available frozen injection in dextrose is frozen; however, this usually will dissolve with little or no agitation upon reaching room temperature, and the potency of ceftazidime sodium frozen injection is not affected. After thawing at room temperature, the containers should be checked for minute leaks by firmly squeezing the bag.

The injection should be discarded if the container seal is not intact or leaks are found or if the solution is cloudy or contains a precipitate. Additives should not be introduced into the injection container.

The injections should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete. Intermittent IV infusions of ceftazidime sodium have generally been infused over 15-30 minutes in adults, neonates, and children. If a Y-type administration set is used, the other solution flowing through the tubing should be discontinued while ceftazidime or ceftazidime sodium is being infused.

Intermittent IV Injection

For direct intermittent IV injection of Fortaz® or Tazidime®, the contents of vials labeled as containing 500 mg, 1 g, or 2 g of ceftazidime may be reconstituted with sterile water for injection as for initial reconstitution for IV infusion to provide solutions containing 100 or 170-180 mg/mL. (See Reconstitution and Administration: Intermittent IV Infusion, in Dosage and Administration.) Alternatively, the manufacturer of Tazicef® states that the contents of a 1-g vial may be reconstituted with 3 mL of sterile water for injection to provide a solution containing approximately 280 mg/mL.

When withdrawing a dose from reconstituted vials of ceftazidime sodium, ensure that the syringe needle opening remains within the solution. Any carbon dioxide bubbles that may be present in the withdrawn solution of ceftazidime sodium should be expelled from the syringe prior to injection. For direct intermittent IV injection of Ceptaz®, the contents of vials labeled as containing 1 or 2 g of ceftazidime may be reconstituted with sterile water for injection as for initial reconstitution for IV infusion to provide solutions containing 90-95 or 170-180 mg/mL, respectively. (See Reconstitution and Administration: Intermittent IV Infusion, in Dosage and Administration.)

The appropriate dose of reconstituted ceftazidime or ceftazidime sodium should be injected over a period of 3-5 minutes directly into a vein or the tubing of a compatible IV solution.

IM Injection

The manufacturers of Fortaz® and Tazidime® state that IM injections of ceftazidime are prepared by adding 1.5 or 3 mL of sterile or bacteriostatic water for injection or 0.5 or 1% lidocaine hydrochloride injection to vials labeled as containing 500 mg or 1 g of ceftazidime, respectively, to provide solutions containing approximately 280 mg/mL. The manufacturer of Tazicef® states that IM injections of the drug are prepared by adding 3 mL of sterile water for injection to a vial labeled as containing 1 g of the drug to provide a solution containing approximately 280 mg/mL.

When withdrawing a dose from reconstituted vials of ceftazidime sodium, ensure that the syringe needle opening remains within the solution. Any carbon dioxide bubbles that may be present in the withdrawn solution of ceftazidime sodium should be expelled from the syringe prior to injection.

The manufacturer of Ceptaz® states that IM injections of ceftazidime are prepared by adding 3 mL of sterile or bacteriostatic water for injection or 0.5 or 1% lidocaine hydrochloride injection to vials labeled as containing 1 g of ceftazidime to provide solutions containing approximately 250 mg/mL. IM injections of ceftazidime or ceftazidime sodium should be made deeply into a large muscle mass, such as the upper outer quadrant of the gluteus maximus or lateral part of the thigh, using usual techniques and precautions.

Intraperitoneal Instillation

For intraperitoneal instillation, a sodium carbonate formulation of ceftazidime powder for injection can be reconstituted with sterile water for injection as for initial reconstitution for IV infusion. (See Reconstitution and Administration: Intermittent IV Infusion, in Dosage and Administration.) The manufacturers of the sodium carbonate formulations of ceftazidime recommend that the drug then be further diluted in a compatible peritoneal dialysis solution to provide a solution containing 250 mg of ceftazidime in each 2 L of dialysis solution.

Dosage

Dosage of ceftazidime and ceftazidime sodium is expressed as anhydrous ceftazidime. Following reconstitution of the commercially available powders for injection containing a mixture of ceftazidime (as the pentahydrate) and sodium carbonate, solutions contain ceftazidime sodium; however, dosage of the drug is expressed in terms of anhydrous ceftazidime.

Adult Dosage

The usual adult dosage of ceftazidime for the treatment of most infections caused by susceptible organisms is 1 g given IV or IM every 8 or 12 hours; however, the dosage and route of administration should be determined by the susceptibility of the causative organism, the severity of the infection, and the condition and renal function of the patient.

The maximum adult dosage of ceftazidime recommended by the manufacturers is 6 g daily. The manufacturers recommend that adults with uncomplicated urinary tract infections receive 250 mg of ceftazidime IV or IM every 12 hours and that adults with complicated urinary tract infections receive 500 mg IV or IM every 8 or 12 hours.

The usual adult dosage of the drug for the treatment of uncomplicated pneumonia or mild skin and skin structure infections is 0.5-1 g IV or IM every 8 hours.

For the treatment of bone and joint infections, the usual adult dosage is 2 g IV every 12 hours.

For the treatment of serious gynecologic and intra-abdominal infections, or severe life-threatening infections (especially in immunocompromised patients), the usual adult dosage of ceftazidime is 2 g IV every 8 hours.

Meningitis

For the treatment of meningitis, the usual dosage of ceftazidime is 2 g IV every 8 hours. Because of a high rate of relapse, anti-infective therapy in patients with meningitis caused by gram-negative bacilli generally should be continued for at least 3 weeks.

Pseudomonas aeruginosa Infections For the treatment of pulmonary infections caused by Pseudomonas aeruginosa in patients with cystic fibrosis and normal renal function, the usual dosage of ceftazidime is 30-50 mg/kg given IV every 8 hours up to a maximum dosage of 6 g daily.

Clinical improvement may occur, but bacteriologic cures should not be expected in patients with chronic respiratory disease and cystic fibrosis.

Empiric Therapy in Febrile Neutropenic Patients

For empiric anti-infective agent therapy in febrile neutropenic patients, the usual dosage of ceftazidime is 100 mg/kg daily given IV in 3 divided doses or 2 g IV every 8 hours either alone or in conjunction with an aminoglycoside (amikacin, gentamicin, tobramycin).

Pediatric Dosage

Children 12 years of age and older may receive the usual adult dosage of ceftazidime.

Because safety of the arginine component of Ceptaz® in younger children has not been established, a sodium carbonate formulation of ceftazidime (e.g., Fortaz®, Tazicef®, Tazidime®) should be used in children younger than 12 years of age.

The usual dosage of ceftazidime (sodium carbonate formulation) for children 1 month to 12 years of age is 25-50 mg/kg IV every 8 hours, depending on the type and severity of infection.

The manufacturers state that the maximum dosage of ceftazidime (sodium carbonate formulation) for children 1 month to 12 years of age is 6 g daily, and that the higher dosage (i.e., 50 mg/kg every 8 hours) should be used in immunocompromised children or children with cystic fibrosis or meningitis.

For empiric anti-infective therapy in febrile neutropenic patients, pediatric patients 2 years of age or older have received ceftazidime in a dosage of 50 mg/kg (maximum 2 g) every 8 hours. The usual dosage of ceftazidime (sodium carbonate formulation) recommended by the manufacturers for neonates up to 4 weeks of age is 30 mg/kg IV every 12 hours. Alternatively, the American Academy of Pediatrics (AAP) recommends that neonates younger than 1 week of age weighing 2 kg or less receive 50 mg/kg of ceftazidime (sodium carbonate formulation) IV every 12 hours and those weighing more than 2 kg receive 50 mg/kg every 8 or 12 hours. The AAP recommends that neonates 1-4 weeks of age receive 50 mg/kg every 8 hours.

Duration of Therapy The duration of ceftazidime therapy depends on the type and severity of infection and should be determined by the clinical and bacteriologic response of the patient.

For most infections, therapy generally should be continued for at least 48 hours after the patient becomes asymptomatic or evidence of eradication of the infection has been obtained.

Complicated infections may require more prolonged therapy.

Dosage in Renal and Hepatic Impairment

In patients with renal impairment, doses and/or frequency of administration of ceftazidime should be modified in response to the degree of renal impairment, severity of the infection, and susceptibility of the causative organism.

Excessive dosage and elevated plasma concentrations of the drug in patients with renal impairment can precipitate serious neurotoxicity (e.g., seizures, encephalopathy, coma, asterixis, neuromuscular excitability, myoclonia).

The manufacturers recommend that adults with creatinine clearances of 50 mL/minute or less receive an initial loading dose of 1 g of ceftazidime and the following maintenance dosage based on the patient’s creatinine clearance: Creatinine Clearance (mL/minute) Dosage 31-50 1 g every 12 h 16-30 1 g every 24 h 6-15 500 mg every 24 h <5 500 mg every 48 h In patients with renal impairment and severe infections who would generally receive a ceftazidime dosage of 6 g daily if their renal function were normal, the manufacturers state that doses in the above table may be increased by 50% or the dosing frequency may be increased appropriately.

Alternatively, some clinicians recommend that adults with creatinine clearances of 30-80 mL/minute receive the usual doses of ceftazidime every 12-24 hours, adults with creatinine clearances of 10-29 mL/minute receive the usual doses every 24-36 hours, and adults with creatinine clearances less than 10 mL/minute receive the usual doses every 36-48 hours. Because ceftazidime is removed by hemodialysis, a supplemental dose of the drug is generally indicated after each dialysis period.

The manufacturers recommend that adults undergoing hemodialysis receive an initial 1-g loading dose of ceftazidime followed by a 1-g dose after each dialysis period. In adults undergoing intraperitoneal dialysis or continuous ambulatory peritoneal dialysis, the manufacturers recommend that an initial 1-g loading dose of ceftazidime be given followed by a 500-mg dose every 24 hours.

Some clinicians recommend that patients undergoing peritoneal dialysis receive 500 mg of ceftazidime every 24 hours and a supplemental 500-mg dose of the drug at the end of each dialysis period. If ceftazidime (as a sodium carbonate formulation) is administered intraperitoneally in the dialysis solution, the manufacturers recommend that 250 mg of the drug be added to each 2 L of dialysis solution.

In children with impaired renal function, the manufacturers of Fortaz®, Tazicef®, and Tazidime® state that the frequency of dosing should be decreased based on the degree of impairment. Modification of the usual dosage of ceftazidime is generally unnecessary in patients with impaired hepatic function, unless renal function is also impaired.

Cautions

Adverse effects reported with ceftazidime are similar to those reported with other cephalosporins. For information on adverse effects reported with cephalosporins, see Cautions in the Cephalosporins General Statement and other monographs in 8:12.06. Ceftazidime is generally well tolerated; adverse effects have been reported in about 9% of patients receiving the drug and have required discontinuance in about 2% of patients.

Hematologic Effects

Eosinophilia has generally been reported in less than 7% of patients receiving ceftazidime. Thrombocytosis has occurred in about 2%1, 2, 48, 217, 260 of patients receiving the drug. Transient leukopenia, neutropenia, thrombocytopenia, agranulocytosis, and lymphocytosis have been reported rarely.

Positive direct antiglobulin (Coombs’) test results have occurred in about 5% of patients receiving ceftazidime. In most reported cases, there was no clinical or laboratory evidence of hemolysis. Mild hemolytic anemia, however, did occur in at least one patient with a positive direct antiglobulin test during ceftazidime therapy; the serum of this patient reacted with ceftazidime-treated erythrocytes, but did not react with untreated erythrocytes.

Cephalosporins have been reported to cause hypothrombinemia. Patients with renal or hepatic impairment, poor nutritional status, or those receiving a protracted course of anti-infective therapy are at particular risk of cephalosporin-induced hypothrombinemia. Prothrombin time should be monitored and vitamin K administered as indicated in patients who are at risk of developing hypothrombinemia.

GI Effects

Adverse GI effects, including diarrhea, nausea, vomiting, abdominal pain, and a metallic taste, have been reported in less than 2% of patients receiving ceftazidime. Clostridium difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis), caused by toxin-producing clostridia resistant to ceftazidime, may occur during or following discontinuance of ceftazidime therapy and ranges in severity from mild to life-threatening. C. difficile toxin has been isolated occasionally from the feces of patients who developed diarrhea and/or colitis during ceftazidime therapy.

Mild cases of C. difficile-associated diarrhea and colitis may respond to discontinuance of ceftazidime alone, but diagnosis and management of moderate to severe cases should include sigmoidoscopy (or other appropriate endoscopic examination), appropriate bacteriologic studies, and treatment with fluid, electrolyte, and protein supplementation as indicated. If diarrhea and colitis is moderate to severe or is not relieved by discontinuance of ceftazidime, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) should be administered. Isolation of the patient may be advisable. Other causes of colitis also should be considered.

Dermatologic and Sensitivity Reactions

Hypersensitivity reactions have been reported in 1-3% of patients receiving ceftazidime and include pruritus, rash (maculopapular or erythematous), urticaria, photosensitivity, angioedema, and fever. Immediate hypersensitivity reactions, including anaphylaxis (manifested as bronchospasm and/or hypotension), have occurred rarely with ceftazidime. Toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme have been reported with cephalosporins, including ceftazidime.If a hypersensitivity reaction occurs during ceftazidime therapy, the drug should be discontinued. Severe acute hypersensitivity reactions should be treated with appropriate therapy (e.g., epinephrine, oxygen, antihistamines, corticosteroids, IV fluids, vasopressors, airway management) as indicated.

Hepatic Effects

Transient increases in serum concentrations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and/or Gamma-glutamyltransferase (?-glutamyl transpeptidase, GGT, GGTP) have been reported in 3-9% of patients receiving ceftazidime. Increased serum concentrations of bilirubin have occurred in less than 1% of patients receiving the drug. Jaundice has been reported with ceftazidime and hepatic dysfunction including cholestasis has been reported with other cephalosporins.

Renal Effects

Transient increases in BUN and/or serum creatinine concentrations have been reported in less than 2% of patients receiving ceftazidime. A transient, mild to moderate decrease in glomerular filtration rate has occurred in a few patients receiving ceftazidime. Although excretion of thermophilic aminopeptidase (alanine aminopeptidase), an enzyme originating from renal proximal tubular cells, was increased slightly in some of these patients, serum creatinine and urinary β2-microglobulin concentrations were generally unaffected, suggesting that ceftazidime did not adversely affect proximal tubular cells. In healthy adults who received 6 g of ceftazidime daily for 3 days, urinary excretion of thermophilic aminopeptidase was unaffected by the drug. It has been suggested that ceftazidime’s potential to slightly decrease glomerular filtration rate may be clinically important in patients with preexisting renal impairment if adequate dosage adjustments are not made in these patients. (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Renal failure has been reported in a few patients receiving ceftazidime; however, a causal relationship to the drug has not been established. Like cephaloridine (a cephalosporin known to be nephrotoxic; no longer commercially available in the US), ceftazidime contains a methylpyridinium at position 3 of the cephalosporin nucleus; however, there is no evidence to date that this group is associated with nephrotoxicity, and the manufacturers state that ceftazidime has not been shown to be nephrotoxic. Nephrotoxicity of cephaloridine apparently results from accumulation of the drug in renal proximal tubular cells; there is no evidence to date that ceftazidime accumulates in renal tubular cells.

Nervous System Effects

Adverse nervous system effects reported with ceftazidime include headache, dizziness, and paresthesia. Seizures have been reported with ceftazidime and other cephalosporins. In addition, coma, encephalopathy, asterixis, hallucinations, neuromuscular excitability, and myoclonia have been reported in patients with renal impairment who received usual dosages of ceftazidime.

Local Effects

Adverse local reactions, including phlebitis and pain or inflammation at the injection site, have been reported in less than 3% of patients receiving ceftazidime. Following IM injection of the drug, pain at the injection site is reportedly mild to moderate for about 2-5 minutes and subsides within 10-20 minutes.

Other Adverse Effects

Other adverse effects that have been reported in less than 1% of patients receiving ceftazidime include candidiasis (e.g., oral thrush) and vaginitis.

Precautions and Contraindications

Ceftazidime shares the toxic potentials of the cephalosporins, and the usual precautions of cephalosporin therapy should be observed. Prior to initiation of therapy with ceftazidime, careful inquiry should be made concerning previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs. There is clinical and laboratory evidence of partial cross-allergenicity among cephalosporins and other b-lactam antibiotics including penicillins and cephamycins.

Ceftazidime is contraindicated in patients who are hypersensitive to any cephalosporin and should be used with caution in patients with a history of hypersensitivity reactions to penicillins. Use of cephalosporins should be avoided in patients who have had an immediate-type (anaphylactic) hypersensitivity reaction to penicillins. Although it has not been proven that allergic reactions to antibiotics are more frequent in atopic individuals, some manufacturers state that ceftazidime should be used with caution in patients with a history of allergy, particularly to drugs. Use of ceftazidime may result in overgrowth of nonsusceptible organisms, especially Candida, Staphylococcus aureus, enterococci, Enterobacter, or Pseudomonas. Resistant strains of Ps. aeruginosa and Enterobacterhave developed during therapy with ceftazidime. (See Resistance.)

Careful observation of the patient during ceftazidime therapy is essential. If superinfection or suprainfection occurs, appropriate therapy should be instituted. Because C. difficile-associated diarrhea and colitis has been reported with the use of cephalosporins or other broad-spectrum anti-infective agents, it should be considered in the differential diagnosis of patients who develop diarrhea during ceftazidime therapy.

Ceftazidime should be used with caution in patients with a history of GI disease, especially colitis. Since resistant strains of Enterobacter have developed during therapy with ceftazidime, some manufacturers recommend periodic susceptibility testing, if clinically appropriate, when ceftazidime therapy is used in the treatment of infections caused by Enterobacteriaceae. High and prolonged serum ceftazidime concentrations may occur if usual dosages of the drug are used in patients with transient or persistent reduction in urinary output because of renal insufficiency.

Doses and/or frequency of administration of ceftazidime should be decreased in patients with transient or persistent renal impairment. (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.) Increased serum ceftazidime concentrations can result in serious adverse nervous system effects (e.g., seizures, encephalopathy, coma, asterixis, neuromuscular excitability, myoclonia). (See Cautions: Nervous System Effects.) Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organisms.

Pediatric Precautions

Safety of the arginine component of Ceptaz® in neonates, infants, and children younger than 12 years of age has not been established. If ceftazidime therapy is indicated in children younger than 12 years of age, a sodium carbonate formulation of ceftazidime (e.g., Fortaz®, Tazicef®, Tazidime®) should be used.

Geriatric Precautions

Clinical studies of ceftazidime did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients. Of the 2221 adults who received ceftazidime in clinical studies, 37% were 65 years of age or older, while 18% were 75 years of age or older.

Although no overall differences in efficacy or safety were observed between geriatric and younger patients and other clinical experience revealed no age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

Ceftazidime is known to be substantially excreted by the kidney, and the risk of ceftazidime-induced toxicity may be greater in patients with renal impairment. Because geriatric patients may have decreased renal function, initial dosage should be selected carefully and it may be useful to monitor renal function. (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Mutagenicity and Carcinogenicity

In vitro studies using microbial (i.e., Ames test) or mammalian cell (i.e., mouse micronucleus) systems have not shown ceftazidime to be mutagenic. Studies have not been performed to date to evaluate the carcinogenic potential of ceftazidime.

Pregnancy, Fertitlity and Lactation

Safe use of ceftazidime during pregnancy has not been definitely established. Reproduction studies in mice and rats using ceftazidime dosages up to 40 times the usual human dosage have not revealed evidence of impaired fertility or harm to the fetus, and a study in rats receiving Ceptaz® at 23 times the human dosage showed no evidence of teratogenicity or embryotoxicity.

There are no adequate or controlled studies using ceftazidime in pregnant women, and the drug should be used during pregnancy only when clearly needed. Because ceftazidime is distributed into milk, sodium carbonate formulations of the drug (Fortaz®, Tazicef®, Tazidime®) should be used with caution in nursing women. It is not known whether the arginine component of Ceptaz® is distributed into milk.

Because the safety of the arginine component of Ceptaz® in nursing infants has not been established, the manufacturer states that a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Probenecid

Concomitant administration of 2 g of oral probenecid does not affect the pharmacokinetics of ceftazidime, presumably because ceftazidime is excreted principally by glomerular filtration.

Anti-infective Agents

Aminoglycosides

In vitro studies indicate that the antibacterial activity of ceftazidime and an aminoglycoside may be additive or synergistic against some strains of Enterobacteriaceae and Pseudomonas aeruginosa. Organisms with high-level resistance to both ceftazidime and the aminoglycoside alone are unlikely to be synergistically inhibited by concomitant use of the drugs.

Concomitant use of aminoglycosides and certain cephalosporins reportedly may increase the risk of nephrotoxicity during therapy. Although this effect has not been reported to date with ceftazidime, the manufacturers suggest that renal function be carefully monitored when an aminoglycoside is used concomitantly with ceftazidime, especially if high aminoglycoside dosage is used or if therapy is prolonged.

b-Lactam Antibiotics

Although a synergistic or partially synergistic effect has occurred in vitro against a few strains of Ps. aeruginosa when ceftazidime and carbenicillin, cefsulodin, mezlocillin, or piperacillin were used concomitantly, use of ceftazidime and another cephalosporin or an extended-spectrum penicillin has generally resulted in an effect that was only slightly additive or indifferent against Ps. aeruginosa. In addition, the combination of ceftazidime and cefoxitin has been antagonistic in vitro against Ps. aeruginosa. The clinical importance is unclear, but concomitant use of ceftazidime and ampicillin in vitro has resulted in antagonism against group B streptococci and Listeria monocytogenes.

Quinolones

Although the clinical importance is unclear, in vitro studies indicate that the combination of ceftazidime and ciprofloxacin exerts a synergistic effect against Burkholderia cepacia. In an in vitro study using B. cepacia isolates from patients with cystic fibrosis, the combination of ceftazidime and ciprofloxacin resulted in increased killing activity against most isolates (except ciprofloxacin-resistant strains).

While a 3-drug combination (ceftazidime, ciprofloxacin, and tobramycin or rifampin) resulted in increased killing activity against B. cepacia isolates compared with ceftazidime alone, this effect was not substantially greater than that attained with the 2-drug combination of ceftazidime and ciprofloxacin.

Other Anti-infectives

In vitro, the combination of ceftazidime and clindamycin has been reported to be neither synergistic nor antagonistic against Bacteroides fragilis. In vitro results indicate that the combination of ceftazidime and metronidazole may be at least partially synergistic against Clostridium, but results against B. fragilis are conflicting. Chloramphenicol has been reported to antagonize the bactericidal activity of b-lactam antibiotics including ceftazidime, in vitro, and the possibility of in vivo antagonism should be considered.

Therefore, the manufacturers recommend that combined therapy with chloramphenicol and ceftazidime be avoided, particularly when bactericidal activity is considered important.

Clavulanic Acid

In vitro studies indicate that the combination of ceftazidime and clavulanic acid, a b-lactamase inhibitor, is synergistic against some strains of B. fragilis resistant to ceftazidime alone. The combination was not effective against other Bacteroides, such as B. distasonis, that are not b-lactamase producers. In vitro studies indicate that the combination of ceftazidime and chloramphenicol may be antagonistic against some organisms.

Diuretics

Although concomitant use of cephalosporins and potent diuretics (e.g., furosemide) reportedly may adversely affect renal function, this effect apparently did not occur when furosemide was used concomitantly with ceftazidime in a few patients.

Laboratory Test Interferences

Immunohematology Tests

Positive direct antiglobulin (Coombs’) test results have been reported in patients receiving ceftazidime. This reaction may interfere with hematologic studies or transfusion cross-matching procedures.

Tests for Glucose

Like most cephalosporins, ceftazidime interferes with urinary glucose determinations using cupric sulfate (e.g., Benedict’s solution, Fehling’s solution, Clinitest®). Urinary glucose determinations using glucose oxidase methods (e.g., Clinistix®) are unaffected by the drug. In addition, ceftazidime does not interfere with glucose oxidase or hexokinase methods used to determine serum glucose concentrations.

Tests for Creatinine

Ceftazidime does not appear to interfere with manual or automated methods used to determine serum or urinary creatinine concentrations, including those using the Jaffe reaction.

Acute Toxcicity

Limited information is available on the acute toxicity of ceftazidime. Inappropriately large doses of parenteral cephalosporins may cause seizures, especially in patients with renal impairment. Overdosage of ceftazidime in patients with renal failure has produced seizures, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia. The drug should be discontinued promptly if seizures occur; anticonvulsant therapy may be administered if indicated. If acute overdosage of ceftazidime occurs, hemodialysis or peritoneal dialysis may be used to enhance elimination of the drug.

Mechanism of Action

Ceftazidime usually is bactericidal in action. Like other cephalosporins, the antibacterial activity of the drug results from inhibition of mucopeptide synthesis in the bacterial cell wall. For information on the mechanism of action of cephalosporins, see Mechanism of Action in the Cephalosporins General Statement 8:12.06. Studies evaluating the binding of ceftazidime to penicillin-binding proteins (PBPs), the target enzymes of b-lactam antibiotics, indicate that ceftazidime binds principally to PBP 3 of Escherichia coli and Pseudomonas aeruginosa.

The drug also has some affinity for PBP 1a of these organisms, but has little affinity for PBPs 2, 4, 5, and 6.45, 50 Ceftazidime binds less well than cefuroxime to PBPs 1, 2, and 3 of Staphylococcus aureus. Spectrum Based on its spectrum of activity, ceftazidime is classified as a third generation cephalosporin.

For information on the classification of cephalosporins and closely related b-lactam antibiotics based on spectra of activity, see Spectrum in the Cephalosporins General Statement 8:12.06. Like other currently available parenteral third generation cephalosporins (e.g., cefoperazone, cefotaxime, ceftizoxime, ceftriaxone), ceftazidime generally is less active in vitro against susceptible staphylococci than first generation cephalosporins but has an expanded spectrum of activity against gram-negative bacteria compared with first and second generation cephalosporins.

The spectrum of activity of ceftazidime resembles that of ceftizoxime, cefotaxime, and ceftriaxone; however, ceftazidime is more active in vitro on a weight basis against Pseudomonas than most other currently available parenteral third generation cephalosporins, but less active in vitro on a weight basis against anaerobes and gram-positive aerobic cocci than these drugs.

In Vitro Susceptibility Testing

Results of in vitro susceptibility tests with ceftazidime for some Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides may be affected by the size of the inoculum. For most organisms there is generally little difference in MICs of ceftazidime when the size of the inoculum is increased from 103 to 105 colony-forming units (CFU) per mL, but MICs of some organisms (e.g., Citrobacter freundii, Enterobacter, Morganella morganii, Proteus, Ps. aeruginosa) may be 8-128 times greater when the size of the inoculum is increased from 105 to 107 CFU/mL. Results of ceftazidime susceptibility tests are generally unaffected by culture media, pH, or presence of serum.

The National Committee for Clinical Laboratory Standards (NCCLS) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to ceftazidime, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated. If results indicate that a clinical isolate has intermediate susceptibility to ceftazidime, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue drug concentrations and response rates may be lower than for strains identified as susceptible.

Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated (e.g., urine) or when a high dosage of the drug can be used. This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.

If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to ceftazidime, the strain is not inhibited by systemic concentrations of the drug achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliably demonstrated in clinical trials. Strains of staphylococci resistant to penicillinase-resistant penicillins should be considered resistant to ceftazidime, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug.

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to ceftazidime, a disk containing 30 mcg of ceftazidime should be used. The cephalosporin class disk containing 30 mcg of cephalothin or disks containing other cephalosporins should not be used to test susceptibility to ceftazidime. When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using NCCLS standardized procedures, Staphylococcus, Enterobacteriaceae, Pseudomonas aeruginosa, or Acinetobacter with growth inhibition zones of 18 mm or greater are susceptible to ceftazidime, those with zones of 15-17 mm have intermediate susceptibility, and those with zones of 14 mm or less are resistant to ceftazidime.

When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using Haemophilus test medium (HTM), Haemophilus with growth inhibition zones of 26 mm or greater should be considered susceptible to ceftazidime. Because of limited data on resistant strains, NCCLS recommends that any Haemophilus isolate that appears to be nonsusceptible to ceftazidime be submitted to a reference laboratory for further testing.

When disk diffusion susceptibility testing is performed according to NCCLS standardized procedures using GC agar base (with 1% defined growth supplement), N. gonorrhoeae with growth inhibition zones of 31 mm or greater should be considered susceptible to ceftazidime. Because of limited data on resistant strains, NCCLS recommends that any N. gonorrhoeae isolate that appears to be nonsusceptible to ceftazidime be submitted to a reference laboratory for further testing.

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus, Enterobacteriaceae, and Ps. aeruginosa and other non-Enterobacteriaceae gram-negative bacilli (e.g., other Pseudomonas spp., Acinetobacter, Stenotrophomonas maltophilia) with MICs of 8 mcg/mL or less are susceptible to ceftazidime, those with MICs of 16 mcg/mL have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater are resistant to the drug.

When dilution susceptibility testing of Haemophilus is performed according to NCCLS standardized procedures using HTM, isolates with MICs of 2 mcg/mL or less should be considered susceptible to ceftazidime.

Because of limited data on resistant strains, NCCLS recommends that any Haemophilus isolates that appear to be nonsusceptible to ceftazidime be submitted to a reference laboratory for further testing. When dilution susceptibility testing of N. gonorrhoeae is performed according to NCCLS standardized procedures using GC agar base (with 1% defined growth supplement), N. gonorrhoeae with MICs of 0.5 mcg/mL or less should be considered susceptible to ceftazidime. Because of limited data on resistant strains, any isolates that appear to be nonsusceptible to ceftazidime be submitted to a reference laboratory for further testing.

Gram-positive Aerobic Bacteria

Ceftazidime generally is active in vitro against the following gram-positive aerobic cocci: penicillinase-producing and nonpenicillinase-producing strains of Staphylococcus aureus and S. epidermidis, Streptococcus pneumoniae, S. pyogenes (group A b-hemolytic streptococci), S. agalactiae (group B streptococci), and viridans streptococci. However, in vitro on a weight basis, ceftazidime is slightly less active than most other currently available third generation cephalosporins against these gram-positive bacteria. Staphylococci resistant to penicillinase-resistant penicillins are resistant to ceftazidime.

Listeria monocytogenes and enterococci, including E. faecalis (formerly S. faecalis), also are generally resistant to the drug. The MIC90 (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of ceftazidime for penicillinase-producing and nonpenicillinase-producing S. aureus is 8-25 mcg/mL. Although the MIC50 of ceftazidime reported for S. epidermidis is 8-16 mcg/mL, the MIC90 of the drug for S. epidermidis or S. saprophyticus usually is 8-50 mcg/mL. The MIC90 of ceftazidime for group A b-hemolytic streptococci or group B streptococci is 0.06-2 mcg/mL. The MIC90 of the drug reported for Streptococcus pneumoniae is 0.13-4 mcg/mL, and the MIC90 reported for viridans streptococci is 3.1-8 mcg/mL. In one study, the MIC50 and MIC90 of ceftazidime for the S. milleri group of viridans streptococci (S. anginosus, S. constellatus, S. intermedius) were 4 and 8 mcg/mL, respectively.

Gram-negative Aerobic Bacteria

Neisseria

Ceftazidime is active in vitro against Neisseria meningitidis and most strains of penicillinase-producing and nonpenicillinase-producing Neisseria gonorrhoeae. Ceftazidime concentrations of 0.001-0.06 mcg/mL generally inhibit N. meningitidis. The MIC90 of ceftazidime is 0.02-0. mcg/mL for nonpenicillinase-producing N. gonorrhoeae and 0.001-0.03 mcg/mL for penicillinase-producing strains of the organism.

Haemophilus

Ceftazidime is active in vitro against most b-lactamase-producing and non-b-lactamase-producing strains of Haemophilus influenzae, H. parainfluenzae, and H. ducreyi. The MIC90 of the drug reported for H. influenzae is 0.1-1 mcg/mL. In one study, the MIC90 of ceftazidime for H. ducreyi was 0.13 mcg/mL.

Enterobacteriaceae

Generally, ceftazidime is active in vitro against the following Enterobacteriaceae: Citrobacter diversus, C. freundii, Enterobacter agglomerans, E. cloacae, E. aerogenes, Escherichia coli, Klebsiella oxytoca, K. pneumoniae, Morganella morganii (formerly Proteus morganii), Proteus mirabilis, P. vulgaris, Providencia rettgeri (formerly Proteus rettgeri), P. stuartii, Serratia marcescens, Salmonella, Shigella, and Yersinia enterocolitica. The MIC90 of ceftazidime for E. coli, Klebsiella (including K. pneumoniae), M. morganii, Providencia, and S. marcescens is 0.2-6.3 mcg/mL. The MIC90 of the drug for P. mirabilis,P. vulgaris, and Y. enterocolitica is 0.05-0. mcg/mL.

The MIC90 of ceftazidime reported for C. diversus is 0.2-1 mcg/mL. The in vitro activity of ceftazidime against C. freundii, however, varies considerably. In some studies the MIC90 of ceftazidime for C. freundii was 0.2-8 mcg/mL, and in other studies it was 32 mcg/mL or greater.

The in vitro activity of ceftazidime against Enterobacter also varies considerably. The MIC90 of ceftazidime reported for E. agglomerans is 0.5-6.3 mcg/mL, and the MIC90 of the drug reported for E. aerogenes is 0.2-32 mcg/mL. In some studies the MIC90of ceftazidime reported for E. cloacae was 0.5-12. mcg/mL, but in other studies it was 32-64 mcg/mL or greater. The MIC90 of ceftazidime reported for Salmonella enteritidis, S. newport, and S. typhi is 0.1-6.5 mcg/mL. In one study, strains of S. typhi resistant to ampicillin and chloramphenicol were susceptible in vitro to ceftazidime concentrations of 0.1-0. mcg/mL. The MIC90 of ceftazidime reported for Shigella, including Sh. flexneri and Sh. sonnei, is 0.12-6.3 mcg/mL.

Pseudomonas

Ceftazidime is active in vitro against Pseudomonas aeruginosa. In vitro on a weight basis, ceftazidime is more active against Ps. aeruginosa than most other cephalosporins. In addition, ceftazidime is active in vitro against some strains of Ps. aeruginosa resistant to other third generation cephalosporins, aminoglycosides, and extended-spectrum penicillins. The MIC90 of ceftazidime reported for Ps. aeruginosa is 0.5-32 mcg/mL. Ceftazidime is also active against Pseudomonas other than Ps. aeruginosa. The MIC90 of ceftazidime reported for Ps. acidovorans, Ps. fluorescens, Ps. putida, and Ps. stutzeri is 0.5-16 mcg/mL.

Burkholderia

Ceftazidime is active in vitro against some strains of Burkholderia cepacia (formerly Ps. cepacia). The MIC50 and MIC90 of ceftazidime reported for some strains of B. cepacia are 2-8 and 4-32 mcg/mL, respectively; however, strains of B. cepacia isolated from patients with cystic fibrosis generally require higher ceftazidime concentrations for in vitro inhibition than strains isolated from patients who do not have cystic fibrosis and many of these strains have MIC90s of 64 mcg/mL or greater and are resistant to the drug. Although the clinical importance is unclear, in vitro studies indicate that the combination of ceftazidime and amikacin or ciprofloxacin exerts a synergistic effect against B. cepacia. (See Quinolones under Drug Interactions: Anti-infective Agents.) Ceftazidime also has in vitro activity against some strains of B. pseudomallei (formerly Ps. pseudomallei). Susceptible strains of B. pseudomallei are inhibited in vitro by ceftazidime concentrations of 1-8 mcg/mL; other strains are resistant to the drug.

Other Gram-Negative Aerobic Bacteria

Ceftazidime has some activity in vitro against Acinetobacter. The MIC90 of ceftazidime reported for A. calcoaceticus, A. lwoffi, and A. baumannii is 8-32 mcg/mL. Moraxella (formerly Branhamella) catarrhalis generally is inhibited in vitro by ceftazidime concentrations of 0.06-0.13 mcg/mL. Some strains of M. osloensis and M. nonliquefaciens are inhibited in vitro by ceftazidime concentrations of 8 mcg/mL. Ceftazidime also is active in vitro against Eikenella corrodens and Pasteurella multocida.

The MIC90 of the drug is 16 mcg/mL for E. corrodens and 0.13-1. mcg/mL for P. multocida. Campylobacter fetus subsp. jejuni, an organism that can be microaerophilic or anaerobic, may be inhibited in vitro by ceftazidime concentrations of 3.1-6.25 mcg/mL.

While some strains of Alcaligenes denitrificans, A. faecalis, and A. xylosoxidans may be inhibited in vitro by ceftazidime concentrations of 1-16 mcg/mL, the MIC90 of the drug reported for Alcaligenes ranges from 2 to more than 64 mcg/mL. In vitro, some strains of Bartonella bacilliformis are inhibited by ceftazidime concentrations of 0.12-0.25 mcg/mL.

The MIC90 of ceftazidime reported for some strains of Chryseobacterium gleum (formerly Flavobacterium gleum, CDC group IIb) and C. indologenes (formerly F. indologenes, CDC group IIb) is 8 mcg/mL and the MIC90 reported for Sphingobacterium multivorum (formerly F. multivorum) is 32 mcg/mL. C. meningosepticum (formerly F. meningosepticum) generally are resistant to ceftazidime. Rare strains of Stenotrophomonas maltophilia (formerly Ps. maltophilia or Xanthomonas maltophilia) are inhibited in vitro by ceftazidime concentrations of 4-16 mcg/mL; however, most strains require ceftazidime concentrations of 32 mcg/mL or greater for in vitro inhibition and are considered resistant to the drug. Although the clinical importance is unclear, in vitro studies indicate that the combination of ceftazidime and a quinolone (e.g., ciprofloxacin, levofloxacin, trovafloxacin) exerts a synergistic bactericidal activity against some strains of S. maltophilia.

Anaerobic Bacteria

Ceftazidime is active in vitro against some gram-positive anaerobic bacteria including some strains of Bifidobacterium, Clostridium, Eubacterium, Lactobacillus, Peptococcus, Peptostreptococcus, and Propionibacterium. The MIC90 of ceftazidime reported for most of these gram-positive anaerobic bacteria is 4-32 mcg/mL. C. perfringens generally is inhibited in vitro by ceftazidime concentrations of 2-16 mcg/mL; however, C. difficile is resistant to the drug. The MIC50 of ceftazidime for Actinomyces is reportedly 6-8 mcg/mL, but the MIC90 is 48-64 mcg/mL.

Ceftazidime has little in vitro activity against gram-negative anaerobic bacteria. Although the MIC90 of ceftazidime reported for Bacteroides melaninogenicus is 4-16 mcg/mL, other Bacteroides (including B. fragilis) are generally resistant to the drug.

The MIC50 of ceftazidime reported for B. fragilis, B. distasonis, B. ovatus, and B. thetaiotaomicron is 8-32 mcg/mL, and the MIC90 of the drug reported for these organisms is usually 64 mcg/mL or greater. Although the MIC50 of ceftazidime reported for Fusobacterium and Veillonella is 4-16 mcg/mL, the MIC90 of the drug for these organisms is 32 mcg/mL or greater and many strains are considered resistant to the drug.

Resistance

For information on possible mechanisms of bacterial resistance to cephalosporins, see Resistance in the Cephalosporins General Statement 8:12.06. Ceftazidime generally is stable against hydrolysis by b-lactamases classified as Richmond-Sykes types I, II, III (TEM type), IV, and V45, 50, 55, 62, 63, 87, 88, 94, 96, 101, 175, 176, 177, 189 and most PSE types.

The drug is hydrolyzed to some extent by chromosomally mediated b-lactamases isolated from Bacteroides and Providencia. Ceftazidime is more stable than cefotaxime or ceftizoxime against hydrolysis by b-lactamases, but as stable as or slightly less stable than cefoxitin. Resistant strains of Enterobacter and Pseudomonas have developed during therapy with ceftazidime. Resistance to ceftazidime in some Enterobacteriaceae (e.g., Enterobacter cloacae, Citrobacter freundii) reportedly results from increased production of chromosomally mediated b-lactamases, nonspecific binding of PBPs, and permeability factors. In vitro studies indicate that resistance to ceftazidime in Ps. aeruginosa, Acinetobacter, and some strains of Serratia is generally related to permeability factors; however, in a few strains of Ps. aeruginosa that developed resistance to ceftazidime during therapy with the drug, resistance appeared to result partly from increased production of chromosomally mediated b-lactamases. Bacteroides are generally resistant to ceftazidime because of permeability factors and because the drug has little affinity for the PBPs of this organism.

Ceftazidime-resistant strains of Klebsiella pneumoniae have been reported, and these strains have been involved in nosocomial outbreaks in hospitals and chronic care facilities.

Resistance in these strains results from acquisition of plasmid-mediated extended-spectrum b-lactamases (TEM- or SHV-derived extended-spectrum b-lactamases). In vitro studies indicate that ceftazidime can induce b-lactamase production in some strains of Enterobacter and Ps. aeruginosa that possess these inducible, chromosomally mediated enzymes; however, the drug is not an efficient inducer when compared with cefoxitin.

Pharmacokinetics

In all studies described in the Pharmacokinetics section, ceftazidime was administered as ceftazidime sodium; dosages and concentrations of the drug are expressed in terms of ceftazidime.

Absorption

Ceftazidime is not absorbed from the GI tract and must be given parenterally.

Following IM administration of a single 0.5- or 1-g dose of ceftazidime in healthy adults, peak serum concentrations of the drug are attained approximately 1 hour after the dose and average 17 or 29-39 mcg/mL, respectively. Following IM injection into the gluteus maximus or vastus lateralis, ceftazidime may be absorbed more slowly in women than in men. In women, peak serum concentrations of the drug may be lower following IM injection into the gluteus maximus than into the vastus lateralis.

Following IV infusion over 20-30 minutes of a single 0.5- or 1-g dose of ceftazidime in healthy men, peak serum concentrations of the drug at completion of the infusion average 42 or 69 mcg/mL, respectively.

IV infusion over 20-30 minutes of a single 2-g dose in healthy adults results in peak serum ceftazidime concentrations at completion of the infusion that average 159-185. mcg/mL and serum concentrations at 0.5, 1, 2, 4, and 6 hours after completion of the infusion that average 87.9.65.2-70.6,38.7,16.7-16.9, and 7.7 mcg/mL, respectively.

Following IV injection over 3-5 minutes of a single 0.5- or 1-g dose of ceftazidime in healthy men, serum concentrations of the drug at 0.25, 0.5, 1, 2, 4, 6, and 8 hours after the dose average 34.1,24.5,17.1,11.2,5.6,2.1-2.4, and 0.9-1.3 mcg/mL, respectively, after the 0.5-g dose and 59.9-83.3,45.3-60.9,32.1-40.9,22.9-23.2,9.7, 4.4-5.3, and 1.9-3.2 mcg/mL, respectively, after the 1-g dose. In adults with suspected gram-negative infections who received a 2-g IV loading dose of ceftazidime followed by 3 g given by continuous IV infusion over 24 hours, steady-state serum concentrations averaged 29. mcg/mL.

Serum concentrations averaged 21.-56. mcg/mL in cystic fibrosis patients 9-25 years of age who received a 7.5- or 10-mg/kg IV loading dose of ceftazidime followed by 3.4 or 4.5 mg/kg hourly given by continuous IV infusion over 24 hours. In neonates 1-15 days of age with infections who received a single 50-mg/kg dose of ceftazidime by IM injection, serum concentrations of the drug averaged 67.2,68.2,42.1,23.7 and 8.9 mcg/mL at 0.5, 1, 3, 6, and 12 hours, respectively, after the dose. In neonates and children with infections who received a single 30-mg/kg dose by IV injection, serum concentrations of ceftazidime averaged 54.., and 18. mcg/mL at 3, 6, and 9 hours, respectively, after the dose in those less than 2 months of age and 26…4, and 3.3 mcg/mL at 3, 5, 7, and 9 hours, respectively, after the dose in those 2-12 months of age. In neonates who received 25-mg/kg doses every 12 hours by IV injection, serum ceftazidime concentrations on the third or fourth day of therapy averaged 81.., and 16. mcg/mL at 0.25, 0.5, 1, 3, 5, and 12 hours, respectively, after a dose. In children 5-14 years of age with cystic fibrosis who received 35-mg/kg doses of ceftazidime every 8 hours by IV injection, serum concentrations averaged 110, 86, 50, 25..1, 4.3, and 2.3 mcg/mL at 0.25, 0.5, 1, 2, 4, 6, and 8 hours, respectively, after the eighth dose. In patients with end-stage chronic renal failure who received a single 1-g dose of ceftazidime via an intraperitoneal catheter, peak serum concentrations were attained 2.75 hours after the dose and averaged 44. mcg/mL; serum ceftazidime concentrations at 0.25, 2, and 8 hours after the dose averaged 14., and 32 mcg/mL, respectively.

Following intraperitoneal administration of a 200-mg dose of ceftazidime in 2 L of dialysis fluid in patients with end-stage chronic renal failure undergoing a 12-hour period of peritoneal dialysis (12 cycles of dialysis, each exchanging 2 L of dialysate for 15-20 minutes), serum ceftazidime concentrations averaged 1.3, 25., and 18. mcg/mL at 1, 12, and 24 hours, respectively, after the start of dialysis. Concentrations of the drug in the dialysis effluent averaged 42. mcg/mL.

Distribution

Following IM or IV administration, ceftazidime is widely distributed into body tissues and fluids including the gallbladder, bone, bile, skeletal muscle, prostatic tissue, endometrium, myometrium, heart, skin, adipose tissue, aqueous humor, and sputum, and pleural, peritoneal, synovial, ascitic, lymphatic, and blister fluids. The volume of distribution of ceftazidime at steady state (Vss) averages 0.18-0.31 L/kg in healthy adults. In neonates 2-9 days of age, the Vss of ceftazidime averaged 0.42-0.55 L/kg. In patients with cystic fibrosis, the volume of distribution of ceftazidime reportedly averages 0.15-0.19 L/kg in the central compartment and 0.17-0.27 L/kg in the peripheral compartment.

Ceftazidime generally diffuses into CSF following IV administration; however, CSF concentrations of the drug are higher in patients with inflamed meninges than in those with uninflamed meninges.

CSF concentrations of ceftazidime do not appear to correlate with CSF leukocyte cell counts or CSF protein concentrations. In adults with meningitis who received 2 g of ceftazidime every 8 hours by IV infusion over 30 minutes, CSF concentrations of the drug on days 2-4 of therapy averaged 9.8 mcg/mL in samples obtained 2 hours after a dose and 9.4 mcg/mL in samples obtained 3 hours after a dose.

On days 11-20 of therapy, when the meninges were presumably healed, CSF concentrations of ceftazidime averaged 4.1 and 7.2 mcg/mL in samples obtained 2 and 3 hours, respectively, after a dose. In neonates with meningitis who received IV ceftazidime in a dosage of 90-150 mg/kg daily, CSF concentrations 2-4 hours after a dose were 22-30 mcg/mL.

Ceftazidime generally is distributed into bile, but biliary concentrations of the drug following IM or IV administration may be lower than concurrent serum concentrations. In women 36-70 years of age undergoing cholecystectomy who received a single 2-g dose of ceftazidime by IV infusion over 15 minutes, ceftazidime concentrations in gallbladder bile 25-160 minutes after the dose ranged from 6.6-58 mcg/mL and concurrent serum concentrations of the drug ranged from 51.6-108 mcg/mL. In another study in patients 34-72 years of age also undergoing cholecystectomy who received a single 1-g IV dose of the drug, ceftazidime concentrations in gallbladder and bile duct bile 60 minutes following the dose averaged 3.9 mcg/mL (range: 0.1-15.2 mcg/mL) and 31.8 mcg/mL (range: 12.5-55.4 mcg/mL), respectively, and concurrent serum concentrations of the drug averaged 36. mcg/mL (range: 23.6-46.8 mcg/mL).

In cystic fibrosis patients aged 5-32 years who received 35- or 50-mg/kg doses of ceftazidime every 8 hours by IV injection, concentrations of ceftazidime in sputum ranged from 0.7-9.8 mcg/mL; peak sputum concentrations were usually attained 1 hour after a dose. In patients undergoing cataract surgery who received a single 2-g dose of ceftazidime by IV injection over 3-5 minutes, aqueous humor concentrations of the drug averaged 2.8, 4, 3.2, 3.4, and 1.9 mcg/mL at 0.5, 1, 2, 4, and 6 hours, respectively, after the dose. Ceftazidime is 5-24% bound to serum proteins.

The degree of protein binding is independent of the concentration of the drug. Ceftazidime crosses the placenta and is distributed into amniotic fluid. Ceftazidime is also distributed into milk. In lactating women with endometritis who received 2 g of ceftazidime IV every 8 hours, concentrations of the drug in milk obtained during days 2-4 of therapy averaged 3.8 mcg/mL immediately prior to a dose and 5.2 and 4.5 mcg/mL at 1 and 3 hours, respectively, after a dose.

Elimination

Plasma concentrations of ceftazidime decline in a biphasic manner. In adults with normal renal and hepatic function, the distribution half-life (t1/2a) of ceftazidime is 0.1-0.6 hours and the elimination half-life (t1/2b) is 1.4-2 hours.

Ceftazidime is not metabolized and is excreted unchanged principally in urine by glomerular filtration. Following IM or IV administration of a single 0.5- or 1-g dose of ceftazidime in adults with normal renal function, 80-90% of the dose is excreted in urine unchanged within 24 hours; approximately 50% of the dose is excreted within 2 hours after the dose.

Serum clearance of ceftazidime averages 98-122 mL/minute in healthy adults. In geriatric patients 63-83 years of age with urinary tract infections, serum clearance of ceftazidime averaged 79 mL/minute and the serum half-life of the drug averaged 2.9 hours. In patients with cystic fibrosis, the serum clearance of ceftazidime ranges from 142-316 mL/minute per 1.73 m; the serum half-life of the drug in these patients, however, ranges from 1-2.2 hours and is generally within the same range as that for healthy individuals.

The serum half-life of ceftazidime is longer in neonates than in older children and adults, but does not appear to be related to gestational age or birthweight. The t1/2b of ceftazidime in neonates 1-23 days of age reportedly ranges from 2.2-4.7 hours. In a group of children 2-12 months of age, the t1/2b of ceftazidime averaged 2 hours.

Serum concentrations of ceftazidime are higher and the serum half-life of the drug is prolonged in patients with impaired renal function. The t1/2? of ceftazidime ranged from 3-4. hours in patients with creatinine clearances of 39-73 mL/minute and 9.4-10. hours in patients with creatinine clearances of 13-27 mL/minute. The t1/2? of ceftazidime in patients with creatinine clearances less than 10 mL/minute ranges from 11.9-35 hours.

The serum half-life of ceftazidime is only slightly prolonged in patients with impaired hepatic function and accumulation of the drug does not generally occur in these patients unless renal function is also impaired. In a group of patients who had normal renal function but impaired hepatic function (e.g., alcoholic cirrhosis, chronic active hepatitis B, biliary cirrhosis), the serum half-life of ceftazidime averaged 2.9 hours. In another group of patients with ascites who had normal renal function, the t1/2a of ceftazidime averaged 0.4 hours and the t1/2b averaged 5.9 hours.

Ceftazidime is readily removed by hemodialysis. The drug is also removed by peritoneal dialysis.

Chemistry and Stability

Chemistry

Ceftazidime is a semisynthetic cephalosporin antibiotic. Like cefepime, cefotaxime, ceftizoxime, and ceftriaxone, ceftazidime is a parenteral aminothiazolyl cephalosporin. Ceftazidime contains an aminothiazolyl side chain at position 7 of the cephalosporin nucleus.

The aminothiazolyl side chain enhances antibacterial activity, particularly against Enterobacteriaceae, and generally results in enhanced stability against b-lactamases. However, ceftazidime contains a carboxypropyl oxyimino group in the side chain rather than the methoxyimino group contained in many aminothiazolyl cephalosporins. This difference results in increased stability against hydrolysis by b-lactamases, increased activity against Pseudomonas, and decreased activity against gram-positive bacteria. Ceftazidime also contains a pyridine at position 3 of the cephalosporin nucleus.

Some commercially available preparations of ceftazidime (Fortaz®, Tazicef®, Tazidime®) are sterile powders for injection containing a mixture of ceftazidime (as the pentahydrate) and sodium carbonate. In these formulations, sodium carbonate has been admixed with ceftazidime to facilitate its dissolution; ceftazidime sodium is formed in situ following reconstitution of the powdered mixture as directed.

The commercially available mixtures of Fortaz®, Tazicef®, and Tazidime® contain 118 mg of sodium carbonate per gram of ceftazidime or 2.3 mEq of sodium per gram of ceftazidime. Ceftazidime is also commercially available as Ceptaz®, a sterile powder for injection containing a mixture of ceftazidime (as the pentahydrate) and arginine. Ceptaz® contains 349 mg of arginine per gram of ceftazidime; the mixture contains no sodium.

Ceftazidime sodium is commercially available as a frozen injection (Fortaz®) in dextrose. Potency of ceftazidime sodium is expressed in terms of ceftazidime, calculated on the anhydrous basis.

Ceftazidime occurs as a white to off-white powder. The drug has solubilities of 5 mg/mL in water and less than 1 mg/mL in alcohol. Ceftazidime has pKas of 1.9, 2.7, and 4.1. When reconstituted as directed, ceftazidime and ceftazidime sodium solutions have pHs of 5-7.5 and 5-8, respectively, and are light yellow to amber in color depending on the diluent used, concentration of the drug, and length of storage.

The commercially available frozen ceftazidime sodium in dextrose injections are light yellow- to amber-colored, nonpyrogenic, sterile solutions of the drug and have osmolalities of approximately 300 mOsm/kg; about 2.2 or 1.6 g of dextrose has been added to the 1- or 2-g injections of ceftazidime, respectively, to adjust osmolality. Ceftazidime sodium in dextrose frozen injections also contain hydrochloric acid and/or sodium hydroxide to adjust pH to 5-7.5; sodium hydroxide neutralizes ceftazidime pentahydrate free acid to the sodium salt.

Stability

The commercially available sterile powders for injection containing mixtures of ceftazidime (as the pentahydrate) and sodium carbonate or ceftazidime (as the pentahydrate) and arginine should be stored at 15-30°C and protected from light.

Commercially available frozen ceftazidime sodium injections (Fortaz®) should be stored at a temperature not greater than -20°C. Ceftazidime powder and solutions of ceftazidime and ceftazidime sodium tend to darken depending on storage conditions; however, color changes do not necessarily indicate loss of potency.

Following reconstitution with sterile water for injection, ceftazidime solutions containing 90-95, 170-180, and 250-280 mg of ceftazidime per mL and most ceftazidime sodium solutions containing 95-100, 170-180, 200, or 280 mg of ceftazidime per mL are stable for 7 days when refrigerated at 4-5°C; the manufacturer of Tazidime® states that these ceftazidime sodium solutions are stable for 10 days when refrigerated.

The manufacturer of Tazicef® states that ceftazidime sodium solutions containing 95-100, 170-180, 200, or 280 mg of ceftazidime per mL in sterile water for injection are stable for 18 hours when stored at room temperature, and the manufacturers of Fortaz® and Tazidime® state that these solutions are stable for 24 hours at room temperature.

The manufacturer of Ceptaz® states that following reconstitution with sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection, solutions containing 100 mg of ceftazidime or less per mL are stable for 24 hours at room temperature and solutions containing more than 100 mg/mL are stable for 18 hours at room temperature.

Following reconstitution with bacteriostatic water for injection or 0.5 or 1% lidocaine hydrochloride injection, Fortaz® or Tazidime® solutions containing 280 mg/mL are stable for 71 or 10 days, respectively, when refrigerated at 4-5°C221, 225 or for 24 hours at room temperature; Ceptaz® solutions containing 250-260 mg/mL in these same diluents are stable for 7 days under refrigeration or 18 hours at room temperature.

Piggyback units of Fortaz® or Tazidime® reconstituted to a concentration of 10 or 20 mg/mL with 0.9% sodium chloride injection or 5% dextrose are stable for 71 or 10 days, respectively, when refrigerated or for 24 hours at room temperature, and those of Tazicef® reconstituted to one of these concentrations with 0.9% sodium chloride are stable for 7 days when refrigerated at 5°C or 18 hours at room temperature.

Ceptaz® solutions reconstituted to a concentration of 170 or 200 mg/mL in sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose are stable for 18 hours at room temperature or 7 days when refrigerated.

The manufacturer of Tazidime® states that when reconstituted as directed in 0.9% sodium chloride injection or 5% dextrose injection, solutions of ceftazidime sodium prepared from ADD-Vantage® vials of the drug are stable for 24 hours at room temperature; these solutions should not be frozen.

The manufacturer of Fortaz® states that when reconstituted as directed in 0.9% sodium chloride injection, 0.45% sodium chloride injection, or 5% dextrose injection, solutions of ceftazidime sodium prepared from ADD-Vantage® vials of the drug are stable for 24 hours at room temperature and for 7 days when refrigerated. Connected ADD-Vantage® vials and diluent containers that have not been activated for dissolution of the drug should be activated and used within 14 days after connection; this period corresponds to that for use of ADD-Vantage® containers following removal of the overwrap.

Following reconstitution with sterile water for injection, extemporaneously prepared ceftazidime sodium solutions containing 280 mg of ceftazidime per mL are stable for 3 months when frozen at -20°C in their original containers.

Extemporaneously prepared Ceptaz® (ceftazidime) solutions containing approximately 170, 200, or 250 mg of ceftazidime per mL in sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection are stable for 6 months when frozen at -20°C in their original containers. A precipitate may form in these frozen solutions; however, this usually will dissolve with little or no agitation upon reaching room temperature, and the potency of the solutions is not affected. Frozen solutions of ceftazidime and ceftazidime sodium should generally be thawed at room temperature.

If warming is necessary to thaw a large volume of frozen solution, the solution should be heated to a maximum of 40°C and care should be taken to avoid heating after thawing is complete.

Once thawed, ceftazidime and ceftazidime sodium solutions should not be refrozen. Once thawed, extemporaneously prepared Fortaz® or Tazicef® solutions are stable for 8 hours at room temperature or 4 days when refrigerated at 4-5°C, and Tazidime® solutions are stable for 24 hours at room temperature or 4 days when refrigerated; thawed solutions of Ceptaz® are stable for 12 hours at room temperature or 7 days when refrigerated; Fortaz® infusion packs reconstituted with sterile water for injection to a concentration of 10 or 20 mg/mL or solutions of the drug that have been reconstituted to a concentration of 100 or 170 mg/mL with 0.9% sodium chloride and transferred to small-volume PVC containers are stable for 6 months at -20°C; once thawed, these solutions are stable for 24 hours at room temperature or 7 days when refrigerated.

Ceptaz® infusion packs reconstituted with sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose to a concentration of 10 or 20 mg/mL; or solutions of the drug that have been reconstituted to a concentration of approximately 90 or 100 mg/mL with 0.9% sodium chloride and transferred to small-volume PVC containers, are stable for 6 months at -20°C. Once these solutions are thawed, they are stable for 18 hours at room temperature or 7 days when refrigerated.

Extemporaneously prepared Tazicef® and Tazidime® solutions containing 95-100 or 180 mg/mL are stable for 3 months at -20°C in their original containers following reconstitution with sterile water for injection or in PVC containers following reconstitution with 0.9% sodium chloride injection or 5% dextrose injection; once thawed, the Tazidime® solutions are stable for 24 hours at room temperature or 4 days when refrigerated, and the Tazicef® solutions are stable for 8 hours at room temperature or 4 days when refrigerated at 5°C. The manufacturer states that the stability of the commercially available frozen ceftazidime sodium injection (Fortaz®) may vary. These injections are stable for at least 90 days from the date of shipment when stored at -20°C.

The frozen injection should be thawed at room temperature or under refrigeration and, once thawed, should not be refrozen. Thawed solutions of the commercially available frozen injection are stable for 24 hours at room temperature (25°C) or 7 days when refrigerated at 5°C.

The commercially available frozen injection of the drug in dextrose is provided in a plastic container fabricated from specially formulated multilayered plastic PL 2040 (Galaxy®). Solutions in contact with the plastic can leach out some of its chemical components in very small amounts within the expiration period of the injection; however, safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.

The manufacturers of Ceptaz®, Fortaz®, Tazicef®, and Tazidime® state that at concentrations of 1-40 mg/mL ceftazidime or ceftazidime sodium is chemically and physically stable for 24 hours at room temperature or for 7 days (Ceptaz®, Fortaz®, Tazicef®) or 10 days (Tazidime®) when refrigerated in the following IV solutions: 0.9% sodium chloride; 1/6 M sodium lactate; 5 or 10% dextrose; 5% dextrose and 0.225, 0.45, or 0.9% sodium chloride; Ringer’s; lactated Ringer’s; 10% invert sugar; or Normosol®-M and 5% dextrose.

The manufacturer of Tazicef® states that at concentrations of 1-40 mg/mL the drug is chemically and physically stable for 18 hours at room temperature or for 7 days when refrigerated at 5°C in the following IV solutions: 0.9% sodium chloride; Ringer’s; lactated Ringer’s; 5 or 10% dextrose; or 5% dextrose and 0.225, 0.45, or 0.9% sodium chloride. The manufacturers state that ceftazidime or ceftazidime sodium solutions in 5% dextrose or 0.9% sodium chloride are stable for at least 6 hours at room temperature in plastic tubing, drip chambers, and volume control devices of common IV infusion sets. Ceftazidime sodium solutions containing 2 mg of ceftazidime per mL in Dianeal® with 1.5% dextrose are stable for 24 hours at room temperature, 10 days when refrigerated at 5°C, and at least 4 hours at 37°C.

Ceftazidime and ceftazidime sodium are potentially physically and/or chemically incompatible with some drugs, including aminoglycosides and vancomycin, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature).

Specialized references should be consulted for specific compatibility information. Sodium bicarbonate injection should not be used as a diluent for ceftazidime or ceftazidime sodium since the drug is less stable in sodium bicarbonate than in other IV solutions. Because of the potential for incompatibility, the manufacturers state that ceftazidime or ceftazidime sodium should not be admixed with aminoglycosides or vancomycin.

The manufacturers of Fortaz® and Tazidime® state that admixtures containing ceftazidime 4 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection and heparin 10 or 50 units/mL, potassium chloride 10 or 40 mEq/L, or cefuroxime 3 mg/mL are stable for 24 hours at room temperature or for 7 days (Fortaz®) or 10 days (Tazidime®) when refrigerated. The manufacturer of Tazicef® states that admixtures containing ceftazidime 20 mg/mL in sterile water for injection and cefazolin 330 mg/mL, cimetidine 150 mg/mL, or heparin 1000 units/mL or admixtures containing ceftazidime 20 mg/mL in 5% dextrose injection and potassium chloride 40 mEq/L are stable for 18 and 24 hours, respectively, at room temperature or 7 days when refrigerated.

The manufacturer of Ceptaz® states that admixtures containing ceftazidime 4 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection and up to 50 units/mL of heparin, up to 40 mEq of potassium chloride, or 3 mg/mL of cefuroxime are stable for 24 hours at room temperature or 7 days when refrigerated. Admixtures containing ceftazidime 20 mg/mL and clindamycin 6 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection, or ceftazidime 20 mg/mL in metronidazole injection 5 mg/mL, are stable for 24 hours at room temperature or 7 days when refrigerated.

For further information on chemistry, mechanism of action, spectrum, resistance, pharmacokinetics, uses, cautions, drug interactions, laboratory test interferences, and dosage and administration of ceftazidime, see the Cephalosporins General Statement 8:12.06.

Preparations

Ceftazidime Parenteral For injection equivalent to anhydrous Fortaz®, ceftazidime 500 mg (with GlaxoSmithKline sodium carbonate) equivalent to anhydrous Ceptaz®, ceftazidime 1 g (with GlaxoSmithKline arginine) equivalent to anhydrous Fortaz®, ceftazidime 1 g (with sodium GlaxoSmithKline carbonate) Tazicef®, Abbott Tazidime®, Lilly equivalent to anhydrous Ceptaz®, ceftazidime 2 g (with GlaxoSmithKline arginine) equivalent to anhydrous Fortaz®, ceftazidime 2 g (with sodium GlaxoSmithKline carbonate) Tazicef®, Abbott Tazidime®, Lilly equivalent to anhydrous Fortaz®, ceftazidime 6 g pharmacy GlaxoSmithKline bulk package (with sodium carbonate) Tazicef®, Abbott Tazidime®, Lilly equivalent to anhydrous Ceptaz®, ceftazidime 10 g pharmacy GlaxoSmithKline bulk package (with arginine) For injection, for equivalent to anhydrous Ceptaz® Infusion Pack, IV infusion ceftazidime 1 g (with GlaxoSmithKline arginine) equivalent to anhydrous Fortaz® ADD-Vantage®, ceftazidime 1 g (with sodium GlaxoSmithKline carbonate) Fortaz® Infusion Pack, GlaxoSmithKline Tazicef® ADD-Vantage®, Abbott Tazicef® Piggyback, Abbott Tazidime® ADD-Vantage®, Lilly Tazidime® Piggyback, Lilly equivalent to anhydrous Ceptaz® Infusion Pack, ceftazidime 2 g (with GlaxoSmithKline arginine) equivalent to anhydrous Fortaz® ADD-Vantage®, ceftazidime 2 g (with sodium GlaxoSmithKline carbonate) Fortaz® Infusion Pack, GlaxoSmithKline Tazicef® ADD-Vantage®, Abbott Tazicef® Piggyback, Abbott Tazidime® ADD-Vantage®, Lilly Tazidime® Piggyback, Lilly Ceftazidime Sodium in Dextrose Parenteral Injection (frozen) equivalent to 20 mg (of Fortaz® in Iso-osmotic , for IV infusion anhydrous ceftazidime) per Dextrose Injection, (Galaxy® mL (1 g) in 4.4% Dextrose [Baxter]) GlaxoSmithKline Tazicef® in Iso-osmotic Dextrose Injection, (Galaxy® [Baxter]) Abbott equivalent to 40 mg (of Fortaz® in Iso-osmotic anhydrous ceftazidime) per Dextrose Injection, (Galaxy® mL (2 g) in 3.2% Dextrose [Baxter]) GlaxoSmithKline Tazicef® in Iso-osmotic Dextrose Injection, (Galaxy® [Baxter]) Abbott