Ceftazidime activity

In the synthesis of ceftazidime (40) (Fig. 8), the protected, preassembled arninothiazole side chain [68672-66-2] (60) is coupled to a protected 7-ACA first and the C-3 displacement step carried out last. By way of contrast, in the synthesis of ceftriaxone (39) (Fig. 9), the preformed C-3 substituent is introduced onto the cephalosporin nucleus in the first step and then the acyl-amino side chain is introduced. This last step is noteworthy for two reasons in that it demonstrates the use of an activated thio ester in the coupling step and that no protecting group chemistry is requited (192,193). 

Near-infrared spectroscopy is quickly becoming a preferred technique for the quantitative identification of an active component within a formulated tablet. In addition, the same spectroscopic measurement can be used to determine water content since the combination band of water displays a fairly large absorption band in the near-IR. In one such study [41] the concentration of ceftazidime pentahydrate and water content in physical mixtures has been determined. Due to the ease of sample preparation, near-IR spectra were collected on 20 samples, and subsequent calibration curves were constructed for active ingredient and water content. An interesting aspect of this study was the determination that the calibration samples must be representative of the production process. When calibration curves were constructed from laboratory samples only, significant prediction errors were noted. When, however, calibration curves were constructed from laboratory and production samples, realistic prediction values were determined ( 5%). 

Van t Veen A, Mouton JW, Gommers D, Kluytmans JAJ, Dekkers P, Lachmann B (1995) Influence of pulmonary surfactant on in vitro bactericidal activities of amoxicillin, ceftazidime, and tobramycin. Antimicrob Agents Chemother 39 329-333. 

U. Imtiaz, E. K. Manavathu, S. Mobashery, S. A. Lerner, Reversal of Clavulanate Resistance Conferred by a Ser-244 Mutant of TEM-1 beta-Lactamase as a Result of a Second Mutation (Arg to Ser at Position 164) That Enhances Activity against Ceftazidime , Antimicrob. Agents Chemother. 1994, 38, 1134-1139. 

Third generation Examples are cefotaxime, cefoperazone, ceftazidime, ceftizoxime, ceftriaxone, cefdinir etc. This generation has greater Gramnegative activity but loses some Gram-positive potency. 

Third-generation cephalosporins (cefotaxim, ceftizoxime, ceftriaxone, ceftazidime, cefop-erazone, and many others) differ in the highly antimicrobial activity against enterobacteria. 

The aminoacyl side chain of this drug, which is analogous to that of ceftazidime, is responsible for the high activity with respect to Gram-negative aerobic bacteria. The spectrum of use of aztreonam is very similar to the antimicrobial spectrum of aminoglycosides, and in the majority of cases it is a potential replacement. 

Penicillins (bactericidal inhibit cell wall crosslinking) e.g., benzylpenicillin, phenoyxmethylpenicillin, ampicillin, amoxicillin, flu-cloxacillin, methicillin, piperacillin Cephalosporins (bactericidal inhibit cell wall crosslinking) e.g., cefaclor, cefalexin, cefradine, cefuroxime, cefazolin, cefotaxime, ceftriaxone, cefoxitin, cefsulodin, ceftazidime, ceftizoxime Monobactams (bactericidal, P-lactam-like activity) e.g., aztreonam... 

Ceftazidime Intravenous, third-generation drug, poor gram-positive activity, good activity versus Pseudomonas... 

Mouton, J., Vinks, A., and Punt, N., Pharmacokinetic-pharmacodynamic modeling of activity of ceftazidime during continuous and intermittent infusion, Antimicrobial Agents and Chemotherapy, Vol. 41, No. 4, 1997, pp. 733-738. 

The class A P-lactamases are a subset of the active-site serine P-lactamases. TEM-1 P-lactamase is a class A enzyme encoded by the ft/ajEM-l gene that is present on the transposons Tn2 and Tn3 (Datta et al, 1965). Epidemiological studies have shown that TEM-1 is the most common plasmid-mediated P-lactamase and is therefore a major determinant of bacterial resistance to P-lactam antibiotics (Wiedemann et al, 1989). Compounding the problem of resistance is the discovery that TEM-1 mutant variants with altered substrate specificity have been identified in natural isolates (Jacoby and Medieros, 1991). These variant enzymes contain from one to three amino acid substitutions that enable the enzyme to hydrolyze the newer extended-spectrum cephalosporin antibiotics such as cefotaxime and ceftazidime (Jacoby and Medieros, 1991). Thus, the selective pressure of antibiotic therapy le s to die creation of new enzymes with expanded hydrolytic capabilities. 

To those beginning work in this field, the study reported by Zhou and Notari on the kinetics of ceftazidime degradation in aqueous solutions may be used as a study design template. First-order rate constants were determined for the hydrolysis of this compound at several pH values and at several temperatures. The kinetics were separated into buffer-independent and buffer-dependent contributions, and the temperature dependence in these was used to calculate the activation energy of the degradation via the Arrhenius equation. Ceftazidime hydrolysis rate constants were calculated as a function of pH, temperature, and buffer by combining the pH-rate expression with the buffer contributions calculated from the buffer catalytic constants and the temperature dependencies. These equations and their parameter values were able to calculate over 90% of the 104 experimentally determined rate constants with errors less than 10%. 

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