Ceftazidime for Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Ceftazidime for Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Bacteremia, Bone infection (Osteomyelitis), Peritonitis, Pneumonia, Septicemia, Skin and Structure Infection, Urinary Tract Infection
Class: Third generation cephalosporins
Form: Intramuscular (IM), Intravenous (IV), Powder
Ingredients: Ceftazidime

Pharmaceutical Information

Drug Substance

Proper Name:Ceftazidime
Chemical Name:Pyridinium, 1-[[7-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-, hydroxide, inner salt,pentahydrate, [6R-[6α,7ß(Z)]].
Structural Formula: 


Molecular Formula:C22H22N6O7S2.5H2
Molecular Weight:636.65 
Description: 

Ceftazidime is a white to cream-coloured crystalline powder. It is soluble in acid, alkali and dimethyl sulfoxide; slightly soluble in water, methanol and dimethylformamide; insoluble in 95% ethanol, ethyl acetate, acetone, 1,-4-dioxan, diethyl ether, toluene, petroleum spirit and chloroform.

Composition: 

Ceftazidime for Injection, USP vials contain a mixture of ceftazidime and sodium carbonate.

The sodium carbonate at a concentration of 118 mg/g of ceftazidime activity has been admixed to facilitate dissolution. The total sodium content of the mixture is approximately 54 mg (2.3 mEq/g of ceftazidime activity).

Solutions of Ceftazidime for Injection range in colour from light yellow to amber, depending upon the diluent and volume used. The pH of freshly reconstituted solutions usually ranges from 5.0 to 7.5.

Reconstitution

NOTE: As with all parenteral drug products, intravenous admixtures should be inspected for clarity of solutions, particulate matter, precipitate, discolouration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used.

For Intramuscular Use

Solutions for Reconstitution: Sterile Water for Injection or, if required, Bacteriostatic Water for Injection, 0.5 to 1.0% Lidocaine Hydrochloride Injection.

Reconstitute as follows:

Reconstitution Table
Vial Size Diluent to be
Added to Vial
Approximate
Available Volume
Approximate Average
Concentration
1.0 g, Vial
(VL7231)
3.0 mL 3.6 mL 280 mg/mL 

Shake well until dissolved. Refer to STABILITY AND STORAGE RECOMMENDATIONS for recommended storage conditions for both dry state and reconstituted solutions.

For Intravenous Use

Solutions for Reconstitution: Sterile Water for Injection.

Reconstitute as follows:

Reconstitution Table
Vial Size Diluent to
be Added to Vial
Approximate
Available Volume
Approximate Average
Concentration
1 g, Vial
(VL7231)
5 or
10 mL
5.6 or
10.6 mL
180 or
95 mg/mL
2 g, Vial
VL7234)
10 mL11.2 mL 180 mg/mL 

Shake well until dissolved. The prepared solution may be further diluted to the desired volume with any of the solutions for i.v. infusion listed below. Refer to STABILITY AND STORAGE RECOMMENDATIONS for recommended storage conditions for both dry state and reconstituted solutions.

For Direct Intravenous Injection

Reconstitute as directed above.

For Intermittent Intravenous Infusion

Reconstitute as directed above for 1 g or 2 g vials of Ceftazidime for Injection, USP.

For Continuous Intravenous Infusion

Reconstitute 1 g or 2 g vials of Ceftazidime for Injection, USP with 10 mL Sterile Water for Injection. The appropriate quantity of the reconstituted solution may be added to an intravenous bottle containing any of the solutions listed below.

Pharmacy Bulk Vial

THE AVAILABILITY OF THE BULK PHARMACY VIAL IS RESTRICTED TO HOSPITALS WITH A RECOGNIZED INTRAVENOUS ADMIXTURE PROGRAM.

Ceftazidime for Injection, USP does not contain any preservatives. The Pharmacy Bulk Vial is intended for multiple dispensing for intravenous use only, employing a single puncture.

Reconstitution Table
Vial SizeDiluent to be Added to VialApproximate Available VolumeApproximate Average Concentration
6 g ,Vial26 mL30 mL200 or
(VL7241)56 mL60 mL100 mg/mL

For 6 g vial (VL7241), following reconstitution with Sterile Water for Injection, the solution should be dispensed and further diluted for use within 8 hours if stored at room temperature (not exceeding 25°C) and 48 hours if refrigerated (2 ‒ 8°C). Any unused reconstituted solution should be discarded after 8 hours if stored at room temperature and after 48 hours if refrigerated . Refer to STABILITY AND STORAGE RECOMMENDATIONS for recommended storage conditions for both dry state and reconstituted solutions.

Solutions for IV Infusion

    0.9% Sodium Chloride Injection

    M/6 Sodium Lactate Injection

    Ringer’s Injection, USP

    Lactated Ringer’s Injection, USP

    5% Dextrose Injection

    5% Dextrose and 0.45% Sodium Chloride Injection

    5% Dextrose and 0.9% Sodium Chloride Injection

    10% Dextrose Injection

    Normosol-M in 5% Dextrose Injection

When Ceftazidime for Injection, USP is dissolved, carbon dioxide is released and a positive pressure develops. For ease of use, please follow the recommended techniques of reconstitution described below.

Solutions of ceftazidime, like those of most beta -lactam antibiotics, should not be added to solutions of aminoglycoside antibiotics because of potential interaction. However, if concurrent therapy with ceftazidime and an aminoglycoside is indicated, each of these antibiotics should be administered in different sites.

Instructions for Reconstitution

For 1 g IM/IV, and 2 g IV vials

  1. Inject the diluent and shake well to dissolve.
  2. Carbon dioxide is released as the antibiotic dissolves, generating pressure within the vial. The solution will become clear within 1 to 2 minutes.
  3. Invert the vial, and completely depress the syringe plunger prior to insertion.
  4. Insert the needle through the vial stopper. Be sure the needle remains within the solution, and withdraw contents of the vial in the usual manner. Pressure in the vial may aid withdrawal.
  5. The withdrawn solution may contain carbon dioxide bubbles which should be expelled from the syringe before injection.

For 6 g Pharmacy Bulk Package

  1. When diluent is being added, the vial must be vented to prevent buildup of pressure due to release of carbon dioxide formed as the antibiotic dissolves. Use standard venting procedures outlined in the venting card for Ceftazidime for Injection, USP.
  2. Inject 26 mL of diluent to provide a solution containing approximately 1 g of ceftazidime for Injection activity per 5 mL. Inject 56 mL of diluent to provide a solution containing approximately 1 g of ceftazidime activity per 10 mL.
  3. Dissolve the antibiotic by gently agitating the solution.
  4. Allow sufficient time (1 – 2 minutes) for carbon dioxide to vent before dispensing solution.
  5. After storage, relieve any additional pressure which may develop in the vial before dispensing.

Stability and Storage Recommendations

Dry Powder

Ceftazidime for Injection, USP in the dry state should be stored between 15 and 30°C and protected from light.

Solutions

1 g (VL7231) and 2 g (VL7234) Vials

Reconstituted solutions should be administered within 12 hours when stored at room temperature, (not exceeding 25°C), and within 48 hours when refrigerated (2 – 8°C), from the time of reconstitution.

6 g (VL7241) Vial

Reconstituted solution and further dilutions should be administered within 8 hours when stored at room temperature (not exceeding 25°C) and within 48 hours if refrigerated (2 – 8°C) from the time of reconstitution. Any unused reconstituted solution should be discarded after 8 hours if stored at room temperature and after 48 hours if refrigerated.

Incompatibility

Ceftazidime for Injection, USP should not be added to blood products, protein hydrolysates or amino acids. Ceftazidime for Injection should not be mixed together with an aminoglycoside.

Availability of Dosage Forms

Vial stoppers do not contain natural rubber latex.

VL 7231:Ceftazidime for Injection, USP 1 g, equivalent to 1 g ceftazidime and 18 mg sodium carbonate, 20 mL rubber-stoppered vial. (Dry Powder.)
VL 7234:eftazidime for Injection, USP 2 g, equivalent to 2 g ceftazidime and 6 mg sodium carbonate, 50 mL rubber-stoppered vial. (Dry Powder.)

Pharmacy Bulk Vial

VL 7241:eftazidime for Injection, USP 6 g, equivalent to 6 g ceftazidime and 8 mg sodium carbonate, 100 mL rubber-stoppered vial. (Dry Powder.)

Microbiology

The in vitro activity of ceftazidime against various Gram-positive and Gram-negative aerobic and anaerobic organisms is shown in Tabl/p>
Table 1
OrganismNo. of Strains Cumulative % of strains inhibited at indicated concentrations (g/mL) 
  0.060.130.250.51.02.04.08.016.031.062.0
GRAM-NEGATIVE AEROBES
Acinetobacter species32--------373478100  
Bordetella pertussis9----78100       
Branhamella catarrhalis743100         
Citrobacter freundii211029627690--95--100  
Citrobacter species18397894100       
Enterobacter aerogenes714--437186--100    
Enterobacter cloacae6210227081868792--949598
Escherichia coli12543749296--9798100   
Haemophilus ducreyi4267100         
Haemophilus influenzae5139829098----100    
Klebsiella pneumoniae10317--27799499----100  
Klebsiella species182844728394100     
Legionella pneumophila*4------100       
Morganella morganii34718594------97--100  
Neisseria gonorrhoea1984--89------95100   
Neisseria meningitidis802100         
Proteus mirabilis10699100         
Proteus rettgeri8617487----100     
Proteus vulgaris3887--97--100      
Providencia species463070788998100     
Pseudomonas aeruginosa1272--518528597100   
Pseudomonas species9424613528899100   
Salmonella species25--896--100      
Serratia marcescens31346697100       
Serratia species69517187100       
Shigella species10105070----90100    
GRAM-POSITIVE AEROBES
Listeria monocytogenes10----------------------
Micrococcus species13--------8233146100  
Staphylococcus epidermidis9----------2278100   
Staphylococcus species            
(methicillin-sensitive)36--------3--64100   
Staphylococcus species            
(methicillin-resistant)24------------4--864100
Streptococcus agalactiae Gr.B.5--100         
Streptococcus faecalis29----------------626976
Streptococcus pneumoniae61783100        
Streptococcus pyogenes875100         
GRAM-NEGATIVE ANAEROBES
Bacteroides fragilis62------------------2155
Bacteroides thetaiotamicron8----------------------
Fusobacterium species15--21--------36--507986
Veillonella species22--9----14--3641648691
GRAM-POSITIVE ANAEROBES
Actinomyces10--------10304060--80100
Bifidobacterium species7--------142943--7186--
Clostridium difficile10------------------1020
Clostridium perfringens29--4----7--18578696100
Peptococcus species46--7--26374363748998100
Peptostreptococcus species21--33--485276--86--95100
Propionibacterium acnes91----------13467698100 

* Legionnaires' Disease has been observed to progress in patients treated with antimicrobial agents possessing demonstrated in vitro activity against Legionnaires' Disease bacterium.

Inoculum Effect

The MIC's of ceftazidime against aerobic bacteria are not significantly affected by changes in inoculum size in the range 102 to 105 CFU/mL. However, increasing the inoculum size to 107 CFU/mL has a pronounced effect on the MIC's for some organisms. In one study, when the inocula of various Enterobacteriaceae (10 Citrobacter species, 10 Enterobacter species, 20 indole-positive Proteus species) were increased in size from 105 to 107 CFU/mL, MIC values increased 8- to 128-fold. The ratios of MBC to MIC are shown in Table 2.

Table 2: Ceftazidime MIC's and MBC's Tested against 110 Bacterial Isolates from 11 Genera
Organisms
(No. Tested)
MIC (µg/mL)MBC (µg/mL)Ratio of Means
Mean90 %Mean90 %MBC/MIC
Citrobacter spp. (10)0.351.00.331.00.94
E. coli (10)0.160.120.180.250.13
Enterobacter spp. (10)0.608.00.658.01.08
K. pneumoniae (10)0.180.120.190.121.06
Proteus Providencia-*Morganella spp. (20)0.150.060.200.121.33
Pr. mirabilis (10)0.050.060.050.061.00
Ser. marcescens (10)0.250.250.300.51.20
Ps. aeruginosa (10)2.404.02.804.01.17
Staph. aureus (10)9.601612.80161.33
Str. faecalis (10)230>256>230>2561.00

*Includes Pr. vulgaris (6), Prov. rettgeri (7) and Morg. morganii (7).

The rates of hydrolysis of ceftazidime and 2 other cephalosporins relative to those of cephaloridine (value 100) by various beta-lactamases are shown in Table 3.

Table 3
NameSourceCFZCFXCAZ
TEM-1E. coli18<10
TEM-2E. coli1900
SHV-1K. pneumoniae<100
OXA-1E. coli13227
OXA-2E. coli15000
OXA-3E. coli80000
K1K. pneumoniae16173
P99E. cloacae1283>1
2046EC. intermedius b3615>1
STH4B. fragilis6101
PSE-1P. aeruginosa14270
PSE-2P. aeruginosa301630
PSE-3P. aeruginosa41<18
PSE-4P. aeruginosa1012
S and AP. aeruginosa11215<1
PC-1S. aureus115030

Abbreviations: CFZ, cefazolin; CFX, cefoxitin; CAZ, ceftazidime.

Development of Resistance

Resistance to ceftazidime has been induced in E. cloacae and C. freundii through successive daily subcultures. Pseudomonas aeruginosa rendered ceftazidime-resistant exhibited cross-resistance to other beta-lactam antibiotics but not to aminoglycosides.

Susceptibility Testing

The standard single-disc susceptibility test (using the 30µg ceftazidime disc) and dilution susceptibility should be interpreted according to the criteria in Table 4.

Table 4
 Zone diameter
(30 µg ceftazidime disc)
Approximate MIC
correlation (mg/L)
Susceptible (susceptible to the usual doses)=18≤ 8
Moderately Susceptible (intermediate)15 - 179 - 31
Resistant≤ 14=32

Organisms should be tested with ceftazidime discs, since ceftazidime has been shown by in vitro tests to be active against certain strains found resistant when other beta-lactam discs are used.

Pharmacology

Human

Intramuscular Injection

Following intramuscular administration of 500 mg and 1 g doses of ceftazidime to normal adult volunteers, the mean peak serum concentrations at approximately 1 hour were 17 mg/L and 39 mg/L respectively. Serum concentration-time curves are shown below.


The average urinary concentration, following 500 mg i.m. administration to 6 patients, was 2,100 mg/L. Mean urinary recovery over 24 hours ranged from 78.9% of a 1g i.m. dose to 84.6% of a 500 mg i.m. dose.


Table 5: Pharmacokinetic Profile of Ceftazidime after i.m. Injection
Dose Peak Serum
Conc.
(mg/L)
Apparent
Volume of
Distribution
Serum
Half-life
(h)
Urinary
Recovery
(%, 24h)
Renal
Clearance
(mL/min)
Single 500mg17 21 2.2 85 90
Single 1g39 17 2.0 79 76
Multiple 1g4417 2.2 -

No drug accumulation was noted after repeated single intramuscular dosing over 10 days. Pharmacokinetic parameters remained unchanged. The addition of lidocaine did not alter the kinetics (see Table 7).

Intravenous Administration

Single doses of 250 mg, 500 mg, 1000 mg and 2000 mg ceftazidime were infused over 30 minutes to six male volunteers. Serum concentration time curves (Figure 3) follow a biexpotential decay.


Mean urinary recovery of unchanged drug over 24 hours was approximately 85%, with over 50% being excreted in the first two to four hours. Figure 4 shows urinary concentrations of two doses of ceftazidime for various collection intervals after infusion.

Table 6: Average pharmacokinetic parameters of ceftazidime after iv infusion
Dose/Route
(IV - Infusion)
Peak
Serum
Conc.
(mg/L)
Apparent
volume of
distribution
(L)
Area under
serum level/
time curve
(mg/L/h)
Serum
half-life
(h)
Dose
recovered
in urine to 24h
(%)
Renal
Clearance
(mL/min)
Plasma
Clearance
(mL/min)
250 mg15.216.233.51.577.5100126
500 mg34.520.268.71.963.277122
1 g76.819.7134.61.869.688126
2 g114.222.5235.61.853.879146

Maximum serum concentrations following rapid intravenous infusions (3 to 5 minutes) were higher than those measured at the conclusion of 30 - 60 minute infusions. The maximum concentration and the area under the curve (AUC) increased proportionately with increasing doses while the elimination half-life (range of 1.5 - 2.01 hours) and renal excretion remained constant. In subjects receiving up to ten days of intravenous ceftazidime, there was no evidence of accumulation or alteration of pharmacokinetics. Addition of probenecid did not alter pharmacokinetics. The apparent volume of distribution and plasma and renal clearance rates remained within the same range as the intramuscular doses. Proportional increases in AUC with increasing doses show that ceftazidime follows linear kinetics.

Excretion and Metabolism

Ceftazidime is not metabolized. Metabolites were not detected either in the serum or in the urine.

Hepatic clearance (i.e., biliary excretion) accounts for less than 1% of the non-renal clearance of ceftazidime in the presence of normally functioning kidneys.

The mean renal clearance of ceftazidime was 86 mL/min (range 46 to 145 mL/min). The calculated plasma clearance of 130 mL/min (range 103 to 199 mL/min) indicated nearly complete elimination of ceftazidime by the renal route. Administration of probenecid prior to dosing had no effect on the elimination of kinetics of ceftazidime, suggesting elimination by glomerular filtration and not by renal tubular secretion.

Protein Binding

In vitro studies with human serum revealed that 5 - 23% of ceftazidime is protein bound and is independent of drug concentration.

Tissue Concentrations

Therapeutic concentrations of ceftazidime in tissues and body fluids are presented in Table 7.

Table 7: Ceftazidime Concentration in Tissues and Body Fluids
   Time of  Average Tissue 
Tissue or FluidDose/RouteNo. of PatientsSample
Post-Dose
or Fluid Level
(µg/mL or µg/g)
Urine

 
500 mg IM60 - 2 hr2100
2 g IV60 - 2 hr12000
Bile2 g IV390 min.36.4
Synovial fluid2 g IV132 hr25.6
Peritoneal fluid2 g IV82 hr48.6
Sputum1 g IV81 hr9
Cerebrospinal fluid (inflamed meninges)2 g q 8h IV5120 min.9.4
Aqueous humor2 g IV131 - 3 hr11
Blister fluid1 g IV72 - 3 hr19.7
Lymphatic fluid1 g IV72 - 3 hr23.4
Bone2 g IV80.67 hr31.1
Heart muscle2 g IV3530 - 280 min.12.7
Skin2 g IV2230 - 180 min.6.6
Skeletal muscle2 g IV3530 - 280 min.9.4
Myometrium2 g IV311 - 2 hr18.7

Concentrations of ceftazidime in the breast milk of 11 puerperal women following intravenous administration of 2 g doses every 8 hours for 5 days were determined by bioassay. Mean (± S.D.) concentrations of ceftazidime averaged 3.8 ± 2.0 µg/mL (before the next dose), 5.2 ± 3.0 µg/mL (1 hour after dosing) and 4.5 ± 1.7 µg/mL (3 hours after dosing). Excretion of ceftazidime into breast milk remained constant between days 2 and 4 of therapy.

Factors Influencing Pharmacokinetics

Sex

Females had a smaller volume of distribution than males attributed to a smaller extra-cellular volume. The time to maximum serum concentration was slightly prolonged in females, and peak serum concentrations were higher than in men following the same dosing.

Pregnancy

Intramuscular injections to pregnant women scheduled for abortions resulted in serum levels of ceftazidime approximately 50% lower than similar doses given to non-pregnant females.

Age

Neonates and Infants

Fifty-three neonates and infants (1 day to 12 months of age) were administered ceftazidime as a single intravenous bolus injection at a mean dose of 31 mg/kg (25.0 - 35.7 mg/kg) in addition to other antimicrobial therapy. Serum levels are presented in Table 10. The mean serum half-life for babies ages 2 months or younger was prolonged (4.2 ± 1.6 h). Those aged greater than 2 months had a half-life of 2.0 ± 0.6h.

Table 8
 Serum levels (µg/mL) at hours after dose (mean ± S.D.)
Age35678
<2 months (n=30)54.1 ± 28.7-31.2 ± 17.9-18.6 ± 2.1
2-12 months (n=23)26.5 ± 10.712.3 ± 7.6-6.4 ± 6.03.3 ± 4.2

In another study pediatric patients (mean age, 3.5 years) with Gram-negative infections received a single intravenous infusion over 15 minutes of either 15 mg/kg (8 patients) or 50 mg/kg (5 patients) of ceftazidime. Serum levels were measured by bioassay. Pharmacokinetic data are presented in Table 9.

Table 9: Pharmacokinetic Parameters in Children
Patien
t
Group
Mean
Age
(months)
Dose
(mg/Kg)
Peak
Serum
Conc.
(mg/L)
Serum
half-life (h)
Vol. of
Distri-
bution
(L/Kg)
Plasma
Clearance
(mL/min/Kg)
A822.51537.81.650.735.03
B557.450186.41.720.523.75
Elderly

Ceftazidime, at a dose of 2g b.i.d., was administered as a bolus intravenous injection to 13 elderly patients with a mean age of 77 years (63 - 83 years) and to 6 younger volunteers (24 - 32 years). A mean serum half-life of 2.9 hours was observed for the elderly patients and 1.75 hours in the young volunteers. The elderly patients were continued on treatment and no accumulation was noted on day 7.

Impaired Renal Function

The relationship between serum elimination half-life and glomerular filtration rate (GFR) is curvilinear. The half-life increases steeply at GFR's less-than 50mL/min/1.73m2 (see Figure 5).


Pharmacokinetics of patients having various degrees of renal insufficiency were compared to those of normal patients following intravenous administration of a lg bolus dose of ceftazidime to 14 patients (mean age 49 years) with severely impaired renal function and those from 8 healthy volunteers (mean age 35 years).

Table 10: Mean Pharmacokinetic Parameters after lg Ceftazidime iv
Group C0
(mg/h/L)
AUCT
(mg/h/L)
B
(h-1)
T1/2ß
(h)
 VdB
(L) 
 UR
(%) 
 GFR
(mL/min)
Volunteers (8)1081520.3781.917.888115
Patients (8)7013600.06116.719.22412
Patients on Dialysis (6)822920.1764.622.20-

Co = Fictive serum concentration at time zero
AUCt = Area under the serum concentration/time curve to infinity
B = Serum elimination rate constant
T1/2B = Serum half-life
VdB = Volume of distribution during the post-distributive phase
UR = Urinary recovery over 24h

In another study, six normal volunteers and four end-stage renal disease (ESRD) patients on hemodialysis were administered a single lg iv dose of ceftazidime. The apparent volumes of distribution were similar in both groups. The terminal half-life in the normal subjects ranged from 1.3 to 1.7 hours, while in the ESRD patients it ranged from 25.5 to 35.4 hours. Dialysis clearance ranged from 27 to 50mL/min, while the total body clearance in the normals ranged from 98 to 184 mL/min.

The elimination half-life measured after peritoneal dialysis was comparable to the value obtained in the post dialysis period of patients undergoing hemodialysis.

Cystic Fibrosis

The pharmacokinetics of an intravenous infusion (20 min) of 50 mg/kg ceftazidime were studied in 10 patients (20.8 ± 4.8 yr, 4 female, 6 males) with cystic fibrosis and 10 normal volunteers (21.6 ± 1.9 yr, 3 females, 7 males). Serum elimination half-lives were 1.76 ± 0.21h in controls and 1.50 ± 0.19h in cystic fibrotics. Total body clearance was 41.9% greater in the cystic fibrosis group (142.4 ±16.9mL/min/1.73m2) compared to controls (100.5 ± 10.3mL/min/1.73m2). Although the fraction of the dose recovered in urine was the same in each group, renal clearance was 40.9% greater in patients with cystic fibrosis (130.1 ± 11.4 and 92.7 ± 11.6mL/min/1.73m2 respectively).

The mechanisms responsible for the altered renal clearance of ceftazidime in cystic fibrotic patients is not known.

Toxicology

Acute Toxicity

The effects produced by single doses of ceftazidime have been studied in mice, rats, dogs, and Rhesus monkeys using intravenous and subcutaneous administration. The results are shown in Table 13.

In the intravenous studies one animal of each species died at the high dose with only minimal signs of toxicity observed, limited to the day of dosing. No deaths or signs of toxicity occurred when ceftazidime was administered subcutaneously to rats.

A single intravenous dose of 1500 mg ceftazidime/kg administered to dogs and monkeys was tolerated with signs of toxicity limited to vomiting and salivation in dogs and soft stools in monkeys.

A comparative study using Glaxo and Lilly ceftazidime was conducted in mice with a single intravenous dose of 2000 mg/kg in mice. Results with both products were similar.

Subchronic Toxicity

Rats

Daily intravenous doses of 100, 300, or 900 mg ceftazidime were administered to rats (15/sex/group) for one month. Doses for this study showed demonstrable toxicity but no deaths at 900 mg/kg.

There were no deaths or toxicologically significant changes in body weight gain, food consumption, or clinical chemistry values. Changes in hematology, slight in degree, including decreases in values of erythrocyte parameters and activated partial thromboplastin time occurred in all dose groups. Slight increases in liver and kidney weight also occurred. Cecomegaly and hyaline droplet formation in the renal cortical tubules were the only treatment-related lesions observed.

Daily intramuscular injections for 12 weeks were well tolerated by rats. All animals survived treatment and no abnormal physical or behavioral symptoms were seen.

Table 11: Acute Toxicity Studies
SpeciesAnimalsDuration of
Study
(Days)
AdministrationDose
Levels
(mg/kg)
Signs of
Toxicity
Results
(LD50 mg/kg)
 MF     
Ceftazidime       
Mouse505014Intravenous516 - 5163Leg weakness and tremors> 5163
Rat303014Intravenous1033 or 2581Leg weakness> 2581
Rat-3014Subcutaneous1033 or 2581NoneLDo > 2581
Dog1114Intravenous1500Vomiting and salivationLDo > 1500
Rhesus Monkey1114Intravenous1500Soft stools and diarrheaLDo > 1500
Mouse-2014Intravenous2000aLeg weakness, poor grooming> 2000
Mouse-2014Intravenous2000bLeg weakness, poor grooming, hypoactivity> 2000

a Glaxo ceftazidime
b Lilly ceftazidime

Erythrocyte counts increased in the 900 mg/kg/day females and decreased in males. Other laboratory parameter changes at the same dose were: decreases in serum alkaline phosphatase, SGPT, hematocrit, and hemaglobin; increases in serum creatinine, bilirubin, potassium, BUN and SGOT; and inconsistent changes in lymphocyte and neutrophil counts.

Increases in serum cholesterol; inconsistent changes in serum proteins; and increases in urinary volume and pH and decreases in specific gravity were observed in both 300 and 900 mg/kg/day groups.

Dogs

Daily intravenous doses of ceftazidime of 250, 500, or 1000 mg/kg were administered to dogs (2/sex/group) for one month. All dogs survived the study and all treated dogs vomited, salivated and had soft and/or mucoid stools. No effects were observed on body weight, clinical chemistry, urinalysis, bone marrow differential counts, or organ weights. A few large platelets and moderate decreases in numbers of platelets in the high dose dogs and mild injection site reactions were the only treatment-related effects. Accumulation of the antibiotic was not observed.

Chronic Toxicity

Rats

Daily subcutaneous doses of 60, 250, or 1000 mg/kg were administered to rats (15/sex/group) for six months. There were no deaths or toxicologically significant changes in food consumption, clinical chemistry, or urinalysis values. Treatment-related effects occurred primarily at the high dose and included depressed weight gain, decreased erythrocyte parameters with compensatory increases in reticulocyte counts and systemic hematopoiesis, increased activated partial thromboplastin time, increased organ weights, cecomegaly, injection site irritation, hemosiderin deposition in renal tubules, renal tubular vacuolar degeneration and the presence of phagocytized amorphous material in renal cortical tubular cytoplasm and in Kupffer cells of the liver.

Dogs

Ceftazidime was administered to dogs (4/sex/group) in daily intravenous doses of 0, 125, 250, or 500 mg/kg for six months. All dogs survived the treatment. No vomiting occurred at any doses, and abnormal stools were seen in the middle and high dose groups. Increases in liver weights and pigmentation of renal cortical tubular ephithelium were seen in the middle and high dose groups. In a second six month study in dogs using intravenous doses up to 850 mg/kg/day, adverse effects of treatment included principally discomfort during injection, salivation and vomiting. Laboratory abnormalities in the mid and high dose groups consisted of decreases in serum gamma-globulin and SGPT, and increases in cholesterol, albumin, and total protein. Post-mortem examinations revealed hepatomegaly, injection phlebitis, proteinaceous droplets in proximal convoluted tubular cells, and infiltration of the prostate.

Mutagenicity Studies

Ceftazidime was evaluated in a battery of in vitro and in vivo tests including Ames test, a modified fluctuation test, a yeast conversion test, DNA repair in rat hepatocytes and mouse micronucleus test. No mutagenic effects were observed.

Reproduction and Teratology Studies Teratology

Mouse

Pregnant mice were given subcutaneous injections of ceftazidime at 1500, 3250 or

6500 mg/kg/day during the period of organogenisis (gestation days 6 - 15). Eight mice from the control group and eight from the 6500 mg/kg/day group were allowed to give birth and raise their young to weaning. The other mice were sacrificed on day 18 of pregnancy and examined.

The overall incidence of skeletal abnormalities was 15% (controls), 20% (3250 mg/Kg ceftazidime) and 24% (6500 mg/kg ceftazidime). These consisted mainly of obliquely fused sternebrae. The incidence of rib variance was significantly higher in the high dose group than in the control group. In the group treated with the high dose (6500 mg/kg), one fetus had extra ribs on cervical vertebrae 6 and 7 and one fetus had a bifid hyoid bone.

The number of live pups/litter and the weights of litters born to mice treated with the high-dose (6500 mg/kg) was significantly lower when compared to controls.

Rabbit

Female Dutch rabbits were given intramuscular injections of 0, 25 mg/kg, 50 mg/kg, 100 mg/kg or 200 mg/kg ceftazidime daily from day 6 to day 18 of pregnancy. On day 29, the rabbits were sacrificed and the uterine contents examined.

Twenty- nine rabbits dosed with ceftazidime were either found dead (18) or had to be destroyed (11) due to ill-health (diarrhea and emaciation) or because they had aborted their fetuses. One rabbit in the control group was found dead on day 10 of pregnancy. The incidence of death was not dose-related (highest incidence occurred in the group given 25 mg/kg/day).

A decrease in body weight was noted during the first week of dosing and continued for the duration of the study in those rabbits receiving doses greater than 25 mg/kg of ceftazidime per day.

Results of the examination of the uterine contents are presented in Table 14 (see below).

Table 12
Observation Control25 mg/kg
ceftazidime 
50 mg/kg
ceftazidime
100 mg/kg
ceftazidime 
200 mg/kg
ceftazidime 
Implantations76666
Resorptions11224
Live Fetuses65443
Live Litter Weight (g)191153136141138
Within Litter Mean

Live Fetuses Weight (g)
31.430.228.626.924.5
Within Litter

Mean Practical Weight

(g)
3.934.563.563.872.91

Two dead fetuses were reported - one in the control group (flexed forepaws) and one in 25 mg/kg/day group. Three fetuses (25 mg/kg group) from a litter of 5 had one or more of the following gross external abnormalities: anencephaly, gastroschisis, 1st and 3rd toes absent from both forepaws, 4th toe on right hind paw absent, tail twisted, craniorachischisis, lower jaw absent, eyes open, fore and hind limb buds present, tail and anogenital papilla present, thoracic and abdominal organs exposed.

Peri- and Postnatal Study

Groups of 20 female rats received a daily sc injection of either 0, 100, 500 or 2500 mg/kg ceftazidime. Animals were dosed from day 17 of pregnancy to the day of parturition and subsequently on days 1 - 21 inclusive postpartum.

No significant adverse reactions were seen during pregnancy with the exception of the high dose (2,500 mg/kg) group which produced large quantities of soft wet feces. During the second and third week of the lactation period the dams treated with ceftazidime gained weight more rapidly than in the control group and this effect was dose-related. At termination (day 21 postpartum), pups in the high-dose group (2,500 mg/kg) had gained significantly (p < 0.05) less weight (47.95 g) than controls (52.23 g). This was observed through lactation.

Fertility and Reproduction

Groups of 20 male and 40 female mice received sc injections of either saline or ceftazidime daily through gametogenesis and mating and in the case of females through pregnancy. Males were treated for 60 days prior to mating and females for 14 days. Half of the pregnant mice were sacrificed on day 18 of pregnancy while the remainder were allowed to litter and rear their young for 21 days. Two pups from each litter were retained to study any effects on fertility of the Fgeneration.

Treatment with ceftazidime had no adverse effect on the fertility of either male or female mice.

A high incidence of skeletal variants seen in all of the groups was due to the large number of fetuses with supernumerary ribs. The incidence of bone variants was significantly higher in the high-dose group (6500 mg/kg/day) as compared to the controls. Throughout lactation, the mean pup weights (F1 generation) for the mid- and high-dose groups (3250 and 6500 mg/kg/day) were

lower than the corresponding control values but the differences did not achieve statistical significance.

There were no significant differences in pregnancy rates for any of the F1 generation groups.

The mean pup weights (F2 generation) during lactation in the high-dose group were consistently

less than those of controls but the differences were not statistically significant and this was attributed to the lighter weights of the dams.

Miscellaneous Studies

Nephrotoxicity Studies in Rabbits

In a comparative study in rabbits, single doses of 354 or 708 mg/kg ceftazidime or 400 or 800 mg/kg cefazolin sodium were administered subcutaneously. Serum concentrations of urea nitrogen, creatinine, glucose, total bilirubin and the activity of alkaline phosphatase and alanine transaminase were used as the indicators of nephrotoxicity. At those doses, there was evidence of nephroxicity with cefazolin but not ceftazidime.

In a similar study, 2000 mg/kg doses of ceftazidime, cefazolin sodium, cefamandole nafate, or cephalothin sodium were given by intravenous infusion. Rabbits treated with cefazolin sodium and cefamandole nafate exhibited severe and mild nephrotoxicity, respectively; while rabbits treated with ceftazidime or cephalothin sodium had no evidence of renal toxicity.

In female mice single sc doses of 8,000 and 10,000 mg/kg ceftazidime produced coagulative necrosis of inner cortical tubules. Male rats given ≥ 4,000 mg/kg produced acute tubular necrosis (inner cortex) and elevations in serum urea nitrogen.

The addition of an aminoglycoside to ceftazidime treatment of male rats did not potentiate the nephrotoxicity of either drug given alone, but involved less outer cortical tubular necrosis than caused by the aminoglycoside alone.

Intramuscular Irritation in Rabbits

In a study in which single intramuscular doses of 0.5 mL sterile water, or 25% aqueous solutions of ceftazidime or cefamandole nafate were given to rabbits, all substances tested, including sterile water, caused muscle necrosis and inflammation. Ceftazidime produced more muscle irritation than sterile water (measured by CPK and histologic endpoints) but less than that produced by cefamandole nafate.

Intravenous Irritation

Postmortem examinations following the 28 week intravenous dose study in dogs demonstrated injection phlebitis.

Hemolysis and Serum Flocculation Tests

These studies were conducted due to the proposed parenteral route of administration. No flocculation was detected in rat or dog blood at a concentration of 250 mg ceftazidime/mL. The same concentration produced only slight in vitro hemolysis in dog blood and no hemolysis in rat blood.

Studies of Ceftazidime Containing Polymer

The possibility that some lots of ceftazidime could generate polymeric impurities was noted in a nephrotoxicity study in rabbits in which unexpected deaths occurred at high doses. Subsequent analytical work showed that the observed toxicity was associated with a high molecular weight polymer. A series of studies in rats, mice and dogs, up to one month in duration, were conducted with ceftazidime containing various levels of polymer. In addition to an apparent enhancement of acute toxicity in mice when administered at a dose of 5000 mg/kg, the most significant finding was foreign material phagocytized in Kupffer cells of the liver. This was found in dogs given 500 or 1000 mg/kg/day of ceftazidime containing 0.6% polymer intravenously for one month. No effects occurred in the 100 mg/kg group. A polymer specification of not more than 0.3% was set for the product based on this study.