Ceftazidime

(BAN, USAN, rINN)
Ceftazidime Chemical formula
Synonyms: Ceftazidim; Ceftazidim pentahydrát; Ceftazidima; Ceftazidimas; Ceftazidimum; Ceftazidimum Pentahydricum; Ceftazydym; GR20263; Keftatsidiimi; LY-139381; Seftazidim. (Z)-(7R)-7-[2-(2Aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate pentahydrate.
Cyrillic synonym: Цефтазидим.

💊 Chemical information

Chemical formula: C22H22N6O7S2,5H2O = 636.7.
CAS — 72558-82-8 (anhydrous ceftazidime); 78439-062 (ceftazidime pentahydrate).
ATC — J01DD02.
ATC Vet — QJ01DD02.

Pharmacopoeias.

In Chin., Eur., Jpn, and US.

Ph. Eur. 6.2

(Ceftazidime). A white or almost white crystalline powder. Slightly soluble in water and in methyl alcohol; practically insoluble in alcohol and in acetone; it dissolves in acid and alkali solutions. A 0.5% solution in water has a pH of 3.0 to 4.0. Store in airtight containers.

USP 31

(Ceftazidime). A white to cream-coloured crystalline powder. Slightly soluble in water, in dimethylformamide, and in methyl alcohol; insoluble in alcohol, in acetone, in chloroform, in dioxan, in ether, in ethyl acetate, and in toluene; soluble in alkali and in dimethyl sulfoxide. pH of a 0.5% solution in water is between 3.0 and 4.0. Store in airtight containers.

Formulation.

Ceftazidime for injection is available as a dry powder containing ceftazidime with sodium carbonate. When reconstituted ceftazidime sodium is formed with the evolution of carbon dioxide. An alternative formulation, ceftazidime with arginine, appears to overcome the problems associated with effervescence. 1 In some countries a frozen injection containing ceftazidime sodium is also used. 1. Stiles ML, et al. Gas production of three brands of ceftazidime. Am J Hosp Pharm 1991; 48: 1727–9.

Incompatibility.

It has been reported that ceftazidime does not cause decreased activity when incubated in solution with gentamicin 1 or tobramycin 2 at 37°, or when mixed with tobramycin in serum. 3 Ceftazidime and tobramycin 4 were also stable for up to 16 hours at room temperature when combined in a glucosecontaining dialysis solution, and for a further 8 hours at 37°. However, licensed product information recommends that ceftazidime, like most other beta lactams, should not be mixed with an aminoglycoside in the same giving set or syringe because of the potential for inactivation of either drug. Ceftazidime is generally considered to be compatible with metronidazole, but degradation of ceftazidime has been reported. 5 Precipitation has occurred with vancomycin 6 and therefore the product information considers it prudent to flush giving sets and intravenous lines between giving the two drugs. However, in one study 7 ceftazidime and/or vancomycin were stable in a glucosecontaining peritoneal dialysis solution when kept for 6 days in a refrigerator or 48 to 72 hours at room temperature, and in a further study 8 the two drugs were stable when combined in similar solutions containing 1.5% or 4.25% glucose for up to 12 hours when stored at 37° and for 24 hours when stored at 4° and 24°. Ceftazidime and teicoplanin 9 were stable in combination in a peritoneal dialysis solution at 37° for 8 hours when it had been previously stored at 4°, but not when previously stored at 25°. Ceftazidime was not stable when mixed in solution with aminophylline. 10 There was some evidence of possible incompatibility with pentamidine. 11 1. Elliott TSJ, et al. Stability of gentamicin in combination with selected new β-lactam antibiotics. J Antimicrob Chemother 1984; 14: 668–9. 2. Elliott TSJ, et al. Stability of tobramycin in combination with selected new β-lactam antibiotics. J Antimicrob Chemother 1986; 17: 680–1. 3. Pennell AT, et al. Effect of ceftazidime, cefotaxime, and cefoperazone on serum tobramycin concentrations. Am J Hosp Pharm 1991; 48: 520–2. 4. Mason NA, et al. Stability of ceftazidime and tobramycin sulfate in peritoneal dialysis solution. Am J Hosp Pharm 1992; 49: 1139–42. 5. Messerschmidt W. Pharmazeutische kompatibilität von ceftazidim und metronidazol. Pharm Ztg 1990; 135: 36–8. 6. Cairns CJ, Robertson J. Incompatibility of ceftazidime and vancomycin. Pharm J 1987; 238: 577. 7. Vaughan LM, Poon CY. Stability of ceftazidime and vancomycin alone and in combination in heparinized and nonheparinized peritoneal dialysis solution. Ann Pharmacother 1994; 28: 572–6. 8. Stamatakis MK, et al. Stability of high-dose vancomycin and ceftazidime in peritoneal dialysis solutions. Am J Health-Syst Pharm 1999; 56: 246–8. 9. Manduru M. et al. Stability of ceftazidime sodium and teicoplanin sodium in a peritoneal dialysis solution. Am J HealthSyst Pharm 1996; 53: 2731–4. 10. Pleasants RA, et al. Compatibility of ceftazidime and aminophylline admixtures for different methods of intravenous infusion. Ann Pharmacother 1992; 26: 1221–6. 11. Lewis JD. El-Gendy A. Cephalosporin-pentamidine isethionate incompatibilities. Am J Health-Syst Pharm 1996; 53: 1462–3.

Stability.

References. 1. Richardson BL, et al. The pharmacy of ceftazidime. J Antimicrob Chemother 1981; 8 (suppl B): 233–6. 2. Brown AF, et al. Freeze thaw stability of ceftazidime. Br J Parenter Ther 1985; 6: 43, 45, 50. 3. Walker SE, Dranitsaris G. Ceftazidime stability in normal saline and dextrose in water. Can J Hosp Pharm 1988; 41: 65–6, 69–71. 4. Wade CS, et al. Stability of ceftazidime and amino acids in parenteral nutrient solutions. Am J Hosp Pharm 1991; 48: 1515–19. 5. Stiles ML, et al. Stability of ceftazidime (with arginine) and of cefuroxime sodium in infusion-pump reservoirs. Am J Hosp Pharm 1992; 49: 2761–4. 6. Stewart JT, et al. Stability of ceftazidime in plastic syringes and glass vials under various storage conditions. Am J Hosp Pharm 1992; 49: 2765–8. 7. Nahata MC, et al. Stability of ceftazidime (with arginine) stored in plastic syringes at three temperatures. Am J Hosp Pharm 1992; 49: 2954–6. 8. Bednar DA, et al. Stability of ceftazidime (with arginine) in an elastomeric infusion device. Am J Health-Syst Pharm 1995; 52: 1912–14. 9. van Doorne H, et al. Ceftazidime degradation rates for predicting stability in a portable infusion-pump reservoir. Am J HealthSyst Pharm 1996; 53: 1302–5. 10. Stendal TL, et al. Drug stability and pyridine generation in ceftazidime injection stored in an elastomeric infusion device. Am J Health-Syst Pharm 1998; 55: 683–5. 11. Servais H, Tulkens PM. Stability and compatibility of ceftazidime administered by continuous infusion to intensive care patients. Antimicrob Agents Chemother 2001; 45: 2643–7.

💊 Adverse Effects and Precautions

As for Cefalotin Sodium. Like cefotaxime, ceftazidime has the potential for colonisation and superinfection with resistant organisms. The risk of superinfection with, for example, Staphylococcus aureus may be higher than with cefotaxime, since ceftazidime is less active against staphylococci.

Breast feeding.

No adverse effects have been seen in breastfed infants whose mothers were receiving ceftazidime, and the American Academy of Pediatrics considers1 that it is therefore usually compatible with breast feeding.
1. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid.; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 25/05/04)

Effects on the blood.

References.
1. Hui CH, Chan LC. Agranulocytosis associated with cephalosporin. BMJ 1993; 307: 484.

Effects on the nervous system.

References.
1. Al-Zahawi MF, et al. Hallucinations in association with ceftazidime. BMJ 1988; 297: 858
2. Jackson GD, Berkovic SF. Ceftazidime encephalopathy: absence status and toxic hallucinations. J Neurol Neurosurg Psychiatry 1992; 55: 333–4
3. Chow KM, et al. Retrospective review of neurotoxicity induced by cefepime and ceftazidime. Pharmacotherapy 2003; 23: 369–73.

Effects on the skin.

References.
1. Vinks SATMM, et al. Photosensitivity due to ambulatory intravenous ceftazidime in cystic fibrosis patient. Lancet 1993; 341: 1221–2.

💊 Interactions

Unlike many other cephalosporins, probenecid has little effect on the renal clearance of ceftazidime.
1. Verhagen CA, et al. The renal clearance of cefuroxime and ceftazidime and the effect of probenecid on their tubular excretion. Br J Clin Pharmacol 1994; 37: 193–7.

💊 Antimicrobial Action

Ceftazidime has a bactericidal action and broad spectrum of activity similar to that of cefotaxime, but increased activity against Pseudomonas spp.; it is less active against staphylococci and streptococci. Unlike cefotaxime it has no active metabolite. Ceftazidime is highly stable to hydrolysis by most beta-lactamases. It is active in vitro against many Gram-negative bacteria including Pseudomonas aeruginosa, Burkholderia pseudomallei (Pseudomonas pseudomallei), and Enterobacteriaceae including Citrobacter and Enterobacter spp., Escherichia coli, Klebsiella spp., both indole-positive and indole-negative Proteus, Providencia, Salmonella, Serratia, and Shigella spp. and Yersinia enterocolitica. Other susceptible Gram-negative bacteria include Haemophilus influenzae, Moraxella catarrhalis (Branhamella catarrhalis), and Neisseria spp. Among Gram-positive bacteria it is active against some staphylococci and streptococci, but meticillin-resistant staphylococci, enterococci, and Listeria monocytogenes are generally resistant. Ceftazidime is active against some anaerobes, although most strains of Bacteroides fragilis and Clostridium difficile are resistant. The activity of ceftazidime against Ps. aeruginosa and some Enterobacteriaceae may be enhanced by aminoglycosides. Antagonism has been reported in vitro between ceftazidime and chloramphenicol. Resistance. As with cefotaxime, resistance may develop during treatment due to the derepression of chromosomally mediated beta-lactamases. It has been noted particularly in Pseudomonas spp. and in Enterobacteriaceae including Citrobacter, Enterobacter spp. and Proteus vulgaris. Resistance may also occur due to the production of plasmid-mediated extended-spectrum
beta-lactamases, particularly in Klebsiella spp. and E. coli.

💊 Pharmacokinetics

Ceftazidime is given by injection as the sodium salt or in solution with arginine. Mean peak plasma concentrations of 17 and 39 micrograms/mL have been reported about 1 hour after intramuscular doses of 0.5 and 1 g of ceftazidime, respectively. Five minutes after intravenous bolus injections of 0.5, 1, and 2 g of ceftazidime, mean plasma concentrations of 45, 90, and 170 micrograms/mL, respectively, have been reported. The plasma half-life of ceftazidime is about 2 hours, but this is prolonged in patients with renal impairment and in neonates. Clearance may be enhanced in patients with cystic fibrosis. It is about 10% bound to plasma proteins. Ceftazidime is widely distributed in body tissues and fluids; therapeutic concentrations are achieved in the CSF when the meninges are inflamed. It crosses the placenta and is distributed into breast milk. Ceftazidime is passively excreted in bile, although only a small proportion is eliminated by this route. It is mainly excreted by the kidneys, almost exclusively by glomerular filtration; probenecid has little effect on the excretion. About 80 to 90% of a dose appears un changed in the urine within 24 hours. It is removed by haemodialysis and peritoneal dialysis.

Cystic fibrosis.

References.
1. Leeder JS, et al. Ceftazidime disposition in acute and stable cystic fibrosis. Clin Pharmacol Ther 1984; 36: 355–62
2. Hedman A, et al. Influence of the glomerular filtration rate on renal clearance of ceftazidime in cystic fibrosis. Clin Pharmacokinet 1988; 15: 57–65
3. Vinks AATMM, et al. Continuous infusion of ceftazidime in cystic fibrosis patients during home treatment: clinical outcome, microbiology and pharmacokinetics. J Antimicrob Chemother 1997; 40: 125–33.

The elderly.

References.
1. LeBel M, et al. Pharmacokinetics of ceftazidime in elderly volunteers. Antimicrob Agents Chemother 1985; 28: 713–15
2. Higbee MD, et al. Pharmacokinetics of ceftazidime in elderly patients. Clin Pharm 1989; 8: 59–62
3. Sirgo MA, Norris S. Ceftazidime in the elderly: appropriateness of twice-daily dosing. DICP Ann Pharmacother 1991; 25: 284–8.

Hepatic impairment.

References.
1. El Touny M, et al. Pharmacokinetics of ceftazidime in patients with liver cirrhosis and ascites. J Antimicrob Chemother 1991; 28: 95–100.

Neonates.

References.
1. van den Anker JN, et al. Ceftazidime pharmacokinetics in preterm infants: effects of renal function and gestational age. Clin Pharmacol Ther 1995; 58: 650–9
2. van den Anker JN, et al. Ceftazidime pharmacokinetics in preterm infants: effect of postnatal age and postnatal exposure to indomethacin. Br J Clin Pharmacol 1995; 40: 439–43
3. van den Anker JN, et al. Once-daily versus twice-daily administration of ceftazidime in the preterm infant. Antimicrob Agents Chemother 1995; 39: 2048–50.

Renal impairment.

References.
1. Welage LS, et al. Pharmacokinetics of ceftazidime in patients with renal insufficiency. Antimicrob Agents Chemother 1984; 25: 201–4
2. Leroy A, et al. Pharmacokinetics of ceftazidime in normal and uremic subjects. Antimicrob Agents Chemother 1984; 25: 638–42
3. Ackerman BH, et al. Effect of decreased renal function on the pharmacokinetics of ceftazidime. Antimicrob Agents Chemother 1984; 25: 785–6
4. Lin N-S, et al. Single- and multiple-dose pharmacokinetics of ceftazidime in infected patients with varying degrees of renal function. J Clin Pharmacol 1989; 29: 331–7
5. Kinowski J-M, et al. Multiple-dose pharmacokinetics of amikacin and ceftazidime in critically ill patients with septic multiple-organ failure during intermittent hemofiltration. Antimicrob Agents Chemother 1993; 37: 464–73
6. Demotes-Mainard F, et al. Pharmacokinetics of intravenous and intraperitoneal ceftazidime in chronic ambulatory peritoneal dialysis. J Clin Pharmacol 1993; 33: 475–9.

💊 Uses and Administration

Ceftazidime is a third-generation cephalosporin antibacterial with enhanced activity against Pseudomonas aeruginosa. It is used in the treatment of susceptible infections especially those due to Pseudomonas spp. They include biliary-tract infections, bone and joint infections, cystic fibrosis (respiratory-tract infections), endophthalmitis, infections in immunocompromised patients (neutropenic patients), melioidosis, meningitis, peritonitis, pneumonia, upper respiratory-tract infections, septicaemia, skin infections may be given in 3 divided doses. Neonates and infants up to 2 months have been given 25 to 60 mg/kg daily in 2 divided doses. In the elderly the dose should generally not exceed 3 g daily. Although not licensed for nebulisation in the UK, the BNFC suggests a dose of 1 g inhaled twice daily for the management of chronic Burkholderia cepacia (Pseudomonas cepacia) infection in patients aged 1 month and older with cystic fibrosis. For details of reduced doses in patients with renal impairment, see below. For surgical infection prophylaxis in patients undergoing prostatic surgery, a dose of 1 g may be given at induction of anaesthesia and repeated if necessary when the catheter is removed. Ceftazidime can be used with an aminoglycoside, another beta lactam such as piperacillin, or vancomycin in patients with severe neutropenia, or, if infection with Bacteroides fragilis is suspected, with an antimicrobial such as clindamycin or metronidazole. The drugs should generally be given separately (see also Incompatibility, above).
1. Rains CP, et al. Ceftazidime: an update of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1995; 49: 577–617.

Administration in renal impairment.

In patients with renal impairment the dosage of ceftazidime may need to be reduced. After a loading dose of 1 g, maintenance doses are based on the creatinine clearance (CC):
CC 31 to 50 mL/minute: 1 g every 12 hours
CC 16 to 30 mL/minute: 1 g every 24 hours
CC 6 to 15 mL/minute: 500 mg every 24 hours
CC less than 5 mL/minute: 500 mg every 48 hours
In severe infections these doses may need to be increased by 50%. In these patients ceftazidime trough serum concentrations should not exceed 40 micrograms/mL. In patients undergoing peritoneal dialysis a loading dose of 1 g may be given followed by 500 mg every 24 hours; ceftazidime sodium may also be added to the dialysis fluid, usually 125 to 250 mg of ceftazidime for 2 litres of dialysis fluid. In patients undergoing haemodialysis a loading dose of 1 g is given and then 0.5 to 1 g after each dialysis period.

💊 Preparations

USP 31: Ceftazidime for Injection; Ceftazidime Injection.

Proprietary Preparations

Arg.: Crima; Fortum; Pluseptic; Tinacef; Zidima; Austral.: Fortum; Austria: Fortum; Kefazim; Belg.: Glazidim; Kefadim†; Braz.: Cefazima†; Ceftanorth†; Ceftazidon; Ceften; Cetaz; Fortaz; Intracef; Kefadim; Roycefax†; Canad.: Ceptaz†; Fortaz; Tazidime†; Chile: Fortum; Kefzim†; Cz.: Fortum; Kefadim†; Denm.: Fortum; Fin.: Glazidim; Fr.: Fortum; Fortumset; Ger.: Fortum; InfectoZidim; Gr.: Cefin; Ceftaridem; Ftazidime; Lemoxol; Malocef; Novocral; Septax; Sipiel; Solvetan; Hong Kong: Fortum; Hung.: Cetazime; Fortum; India: Cefazid; Ceftaz; Ceftidin; Fortum; Zytaz; Indon.: Caltum; Ceftum; Cetazum; Extimon; Fortum; Lacedim; Pharodime; Sodime; Thidim; Zefidim; Zibac; Zidifec; Irl.: Fortum; Israel: Fortum; Ital.: Cedizim; Ceftim; Dizatec; Etazim; Fribat; Glazidim; Liotixil; Panzid; Spectrum; Starcef; Tazidif; Tottizim; Malaysia: Cef-4; Fortum; Mex.: Fenit; Fortum; Izadima; Lezidim†; Tagal; Taloken; Taxifur; Zadolina; Zidicef; Neth.: Fortum; Tazalux; Norw.: Fortum; NZ: Fortum; Philipp.: Baxidyme; Dimzef; Fortum; Forzid; Tazicef; Tazidan; Tazidem; Uniranz; Zadim; Zeptrigen; Pol.: Biotum; Fortum; Mirocef; Port.: Cefortam; Ceftazim; Zidimox; Rus.: Bestum (Бестум); Fortum (Фортум); Lorazidime (Лоразидим); S.Afr.: Fortum; Kefzim†; Taziject; Singapore: Cefazime; Fortum; Spain: Fortam; Kefamin; Swed.: Fortum; Switz.: Fortam; Thai.: CEF-4; Cef-Dime; Cefodime; Dimase; Fortadim; Fortum; Forzid; Fournox†; Zeftam; Turk.: Fortum; Iesetum; UAE: Negacef; UK: Fortum; Kefadim; USA: Ceptaz; Fortaz; Tazicef; Tazidime; Venez.: Betazidim; Biozidima; Cefgram; Fortum; Kesterina†.
Published January 13, 2019.