Ceftazidime: Antimicrobial Activity, Susceptibility, Administration and Dosage, Clinical Uses etc.

Ceftazidime is a semisynthetic third-generation cephalosporin with notable activity against Pseudomonas aeruginosa (O’Callaghan et al., 1980; Verbist and Verhaegen, 1981). This drug it is a parenteral antibiotic administered as a monosodium salt because it is highly soluble in water. It is hydrolyzed by a variety of beta-lactamases including extended-spectrum beta-lactamases (ESBLs), AmpC betalactamases and most of the carbapenemases. There is the potential to add a beta-lactamase inhibitor to ceftazidime to restore activity lost by the effects of beta-lactamases. Thus far, ceftazidime plus NXL-104 is being studied, and ceftazidime plus a variety of conventional inhibitors is available in India. These combinations will not be discussed in detail in this chapter, given their limited availability.

The molecular weight of ceftazidime is 546.58 and its chemical formula is C22H22N6O7S2. The structure of ceftazidime is given in Figure 30.1.

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

Gram-positive aerobic bacteria

No interpretative criteria for antimicrobial susceptibility tests have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) regarding ceftazidime and Gram-positive bacteria, whereas the Clinical and Laboratory Standards Institute (CLSI) has criteria only for ceftazidime and Staphylococcus spp. (Table 30.1). Data regarding wild-type Gram-positive isolates are limited to a few species of streptococci (Table 30.2). However, ceftazidime MIC values for wildtype and clinical isolates of Streptococcus pneumoniae, S. pyogenes, and S. viridans group are consistently higher than those of ceftriaxone, cefotaxime, and cefepime (Tables 30.2 and 30.3) (Bell et al., 2002; Fritsche et al., 2003).

Gram-negative aerobic bacteria

Wild-type isolates of P. aeruginosa are fully susceptible to ceftazidime, whereas clinical strains express resistance in 10–40% of cases, depending on the country of isolation (Tables 30.4 and 30.5). Ceftazidime is often recognized as the most effective parenteral cephem against P. aeruginosa. However, a comparison of epidemiologic data obtained during large multicenter studies shows that ceftazidime expresses MIC90s generally higher than the fourth-generation cephalosporin cefepime (see Chapter 32, Cefepime) (Mathai et al., 2001; Gales et al., 2002; Turnidge et al., 2002; Hoban et al., 2003; Fedler et al., 2006; Jones et al., 2007; Moet et al., 2007). Only two studies recorded the same MICs50/90 between the two drugs (Rennie et al., 2003; Sader et al., 2003), and only one report showed better performances for ceftazidime (Rhomberg and Jones, 2007).

At least 30% of wild-type Acinetobacter spp. isolates express resistance against ceftazidime (Table 30.4). Furthermore, clinical isolates of A. baumannii are frequently resistant to ceftazidime (Table 30.5). No CLSI criteria for S. maltophilia have been established regarding ceftazidime (Table 30.1). However, the majority of strains show MICs Z8 mg/ml (Table 30.5). Notably, according to the EUCAST criteria, the use of ceftazidime against infections due to Acinetobacter spp. and S. maltophilia should be considered inappropriate (Table 30.3).

Wild-type and clinical isolates of Haemophilus influenzae appear fully susceptible to ceftazidime (Tables 30.4 and 30.5). With regard to Moraxella catarrhalis, no interpretative criteria have been established and clinical data are insufficient (Table 30.1). No CLSI and EUCAST criteria have been established for ceftazidime against N. meningitidis (Table 30.3). According to the CLSI criteria, N. gonorrhoeae appear frequently susceptible to ceftazidime, but data regarding clinical strains are scarce (Table 30.5).

Anaerobic bacteria

Most anaerobes are resistant to ceftazidime. Clostridium spp. show high MIC values for ceftazidime (Table 30.3) (Larsson et al., 1985; Steyaert et al., 1999; Loza et al., 2003). Peptostreptococcus spp. also show MIC values for ceftazidime which are markedly elevated (MIC90 Z16 mg/ ml) (Kuriyama et al., 2002; Loza et al., 2003). Data regarding the remaining Gram-positive anaerobes are scarce. The activity of ceftazidime appears moderate against Gram-negative anaerobes such as Fusobacterium and Prevotella spp., whereas B. fragilis and other Bacteroides spp. are resistant (Kuriyama et al., 2002; Loza et al., 2003).

Other bacteria

Ceftazidime is inactive against Chlamydia, Mycoplasma, and Rickettsia. b. Emerging resistance and cross-resistance Ceftazidime-resistant P. aeruginosa strains can be selected in vitro by exposing the organism to various concentrations of ceftazidime (Piddock and Traynor, 1991; Bagge et al., 2000). Such strains can also arise when ceftazidime is used for infections in experimental animals (Bayer et al., 1987; Pechere and Vladoianu, 1992; Fantin et al., 1994), and they can also arise during treatment in humans (King et al., 1983; Paterson and Bonomo, 2005). Once the drug is used widely in hospital settings, P. aeruginosa-resistant strains (and some other Gramnegative bacteria such as Enterobacter spp.) become more prevalent (Lee et al., 1999; Paterson and Bonomo, 2005). Once restrictions are placed on the use of ceftazidime and other cephems, susceptibility of P. aeruginosa isolates partially recovers (Gruson et al., 2000; Regal et al., 2003; Brahmi et al., 2006).

c. In vitro synergy and antagonism

Although synergy can be demonstrated in vitro between ceftazidime and aminoglycosides, the clinical significance of this phenomenon is not clear.

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

Ceftazidime is given by either the intramuscular (i.m.) or much more commonly, the intravenous (i.v.) route. The following scheduled dosages can be used for ceftazidime treatment: uncomplicated urinary tract infections (250–500 mg i.v. every 12 hours); bone and joint infections (2 g i.v. every 8–12 hours); complicated urinary tract infections (500 mg–1 g i.v. or i.m. every 8–12 hours); uncomplicated pneumonia, mild skin and skin-structure infections (500 mg–1 g i.v. or i.m. every 8 hours); serious gynecologic and intra-abdominal infections, meningitis, and very severe life-threatening infections, especially in immunocompromised patients (2 g i.v. every 8 hours); lung infections caused by nonfermenting Gram-negative bacilli in patients with CF with normal renal functions (30–50 mg/kg i.v. every 8 hours with a maximum of 6 g/day). In all cases, individual doses in excess of 1 g should be administered i.v.

b. Newborn infants and children

The usual dosage range for children aged over 12 months is 25– 150 mg/kg/day given every 8 hours (up to a maximum of 6 g/day). The maximum daily dosage may be given to children with very serious infections those who are immunocompromised, who suffer from CF, or from septicemia and meningitis.

c. Altered dosages Impaired renal function

In these patients, dosage reduction is necessary because the elimination rate of ceftazidime is considerably decreased. An excellent linear correlation between creatinine clearance (CLCr) and ceftazidime clearance in patients with different levels of renal failure has been demonstrated (Ackerman et al., 1984; Leroy et al., 1984).

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Ceftazidime is not bioavailable when given orally. The serum protein binding of ceftazidime is only 17% (O’Callaghan et al., 1980; Mulhall and de Louvois, 1985).

b. Drug distribution

The pharmacokinetic of ceftazidime was investigated in human volunteers who received doses of 0.5, 1, and 2 g of drug by a 5- minute i.v. infusion. On average, the half-life of ceftazidime was 1.95 hours, volume of distribution was 0.23 l/kg, and body clearance was 131 ml/min. Mean serum levels after a dose of 1 g ceftazidime were 107, 4.4, 2.1, and 0.5 mg/ml after 10 minutes, 6, 8, and 12 hours, respectively.

Distribution of the drug in the body

Cerebrospinal fluid

The penetration of ceftazidime into CSF was studied in patients after a 2 g i.v. bolus injection. In patients with normal meninges the penetration was less than 1 mg/ml. In patients with meningitis (n = 5) levels of 18, 17, 16, 1, and 0.8 mg/ml were found (Walstad et al., 1983). In a similar study, after 2 or 3 g i.v. doses which produced similar serum concentrations, CSF levels were substantially lower in patients without meningitis (mean 0.8 mg/ml) than in those with meningitis (mean 22.6 mg/ml). 

Eyes

The intraocular penetration of ceftazidime was studied following i.v. injection of 50 mg/kg in rabbits after acute endophthalmitis had been unilaterally induced. The mean penetration into aqueous humour of the eyes with and without endophthalmitis was 64% and 10%, respectively. In the vitreous body, the corresponding penetration was 5% and 1% (Walstad et al., 1987).

Lower respiratory tract

Penetration of ceftazidime into lung tissue of patients subjected to pulmonary surgery was evaluated. Samples of lung tissue were taken 1 and 2 hours after antibiotic administration. The mean lung tissue levels in patients receiving a single i.v. injection of 1 g ceftazidime were 16.3 and 10 mg/g, respectively. The percentage of penetration from serum was 38.3% and 35.3%, respectively.

c. Clinically important pharmacokinetic and pharmacodynamic features

Since ceftazidime has concentration-independent killing, bacterial eradication is a function of the time the serum drug concentration remains above the MIC of the infecting organism. In fact, it is well documented that clinical success is accomplished when adequate percentage TWMIC is achieved for infecting organisms. For ceftazidime and other cephalosporins, the cumulative fractions of response (CFR) for bacteriostatic and bactericidal targets (percentage TWMIC) are Z40% and 70%, respectively (Craig, 1998).

d. Excretion

The major route of excretion of ceftazidime is via the kidneys. Four to six hours after 0.5 and 1 g i.v. ceftazidime doses were administered, urinary levels of the drug were 120.9 and 502.8 mg/ml, respectively.
Urinary recovery rates during 24 hours were 90.3% and 88.7%, respectively. As concomitant administration of probenecid did not alter either serum levels or urinary recovery, the mechanism of renal excretion was considered to be mainly by glomerular filtration. No active metabolites were detected in urine (Saito, 1983).

TOXICITY

Similar to other cephalosporins, ceftazidime is a drug with low toxicity. The most common adverse effects are local reactions following i.v. injection, allergic reactions, and gastrointestinal reactions. Local effects, reported in fewer than 2% of patients, were phlebitis and inflammation at the site of injection. Hypersensitivity reactions, reported in 2% of patients, were pruritus, rash, and fever. Immediate reactions, generally manifested by rash and/or pruritus, occurred in less than 0.5% of patients. Toxic epidermal necrolysis, Stevens–Johnson syndrome, and erythema multiforme have also been reported. Angioedema, anaphylaxis (bronchospasm and/or hypotension), severe allergic reactions (e.g. cardiopulmonary arrest), urticaria, and pain at injection site have been reported very rarely.

CLINICAL USES OF THE DRUG

a. Empiric treatment of fever in neutropenic oncology patients

Ceftazidime is active against most aerobic Gram-negative bacilli, including P. aeruginosa, and thus ceftazidime monotherapy has been widely used. However, in recent years, multidrug-resistant Gramnegative bacilli and methicillin-resistant Staphylococcus spp. have become more common in these patients, rendering the use of ceftazidime monotherapy potentially unsafe in some circumstances (Ramphal et al., 1996; Picazo, 2005).

b. Serious bacterial infections, including bacteremia and pneumoniab

Ceftazidime in a dose of 2 g i.v. every 8 hours has been found to be effective for the treatment of such severe infections, which normally occur in the hospital setting (Clumeck et al., 1983; Eron et al., 1983; Francioli et al., 1983; Maslow et al., 1983). However, in the case of infections due to strains expressing high MICs against ceftazidime (e.g. ESBL and/or AmpC producers), standard therapeutic regimens might be unable to guarantee a good clinical outcome (Craig, 1998).

c. Meningitis

Ceftazidime has historically been effective in H. influenzae, E. coli, and other forms of enterobacterial meningitis (Elliott et al., 1986; Hatch et al., 1986). However, either cefotaxime or ceftriaxone should be preferred. For P. aeruginosa meningitis, ceftazidime is one of the drugs of choice, but an aminoglycoside should be added in some cases (Fong and Tomkins, 1985; Gopal and Burke, 1990; Rodriguez et al., 1990). Ceftazidime is unlikely to be effective in the management of Acinetobacter meningitis.

d. Endocarditis

Human data regarding endocarditis are rare, and only a few clinical cases have been described. Successful therapy of P. aeruginosa endocarditis with ceftazidime and tobramycin has been observed (Cabinian and Kaatz, 1987). Ceftazidime and amikacin were administered in a P. aeruginosa rabbit endocarditis model using an i.v. infusion pump to simulate human serum concentrations for the following regimens: CI of 4, 6, or 8 g of ceftazidime every 24 hours or II of 2 g every 8 hours either alone or in combination with amikacin (15 mg/kg every 24 hours).

e. Urinary tract infection

Cefepime and ceftazidime are equally safe and efficacious treatment for pyelonephritis among pediatric patients. The efficacy of cefepime were compared with those of ceftazidime for treatment of pyelonephritis in pediatric patients (both administered i.v. at 50 mg/kg every 8 hours). Bacteriologic eradication was achieved in 96% and 94% of cefepime and ceftazidime groups, respectively. A satisfactory clinical response occurred in 98% and 96% of cefepime and ceftazidime patients, respectively (Schaad et al., 1998).

f. Melioidosis

Ceftazidime is often regarded as a drug of choice for melioidosis. The best clinical performances have been obtained using an association with trimethoprim–sulfamethoxazole. Other cephalosporins are less active. Only carbapenems provided equivalent clinical results during large randomized trials (White, 2003; Chierakul et al., 2005).

g. Osteomyelitis

The cases of 28 patients who received ceftazidime for biopsy cultureproven osteomyelitis were reviewed. These cases all involved infection caused by Gram-negative aerobic bacilli, the most frequent agent (83% of patients) being P. aeruginosa. A regimen of 2 g every 12 hours was used for most patients. The overall cure rates were 77% for acute disease and 60% for chronic disease (Bach and Cocchetto, 1987).

h. Ear and sinus infections

In an Italian study, ceftazidime showed very substantial clinical efficacy for otitis media, with positive results in 97% of cases treated, which is particularly significant if one considers that roughly 64% of the infections were caused by ‘‘difficult’’ Gram-negative bacteria (49% by Pseudomonas spp.) (Vellucci et al., 1987). 

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