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    Evaluation of New Drugs

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    veronica

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    of 12
    fe Evaluations of New Drugs a7 Ceftizoxime: A Beta-Lactamase-Stable, Broad-Spectrum Cephalosporin Pharmacokinetics, Adverse Effects and Cl Harold C. Neu, M.D. ical Use Ceftizoxime is an iminomethoxy aminothiazoiyl cephalosporin that inhibits a wide varity of aerobic, anaetcbie gram-positive ané gram-negative bacteria, The majority of Entorobacteriaceae are inhibited by= 1 ug't as are streptococcal species withthe exception of Streptococcus faecalis. Staphylococcus aureus are inhibited by 3-8 ug'ml, while methicilin-resislantS. aureus are resistant, Bacteroides fragilis axe inhibited by 16-64 ug ml. tinbits Pseudomonas aeruginosa al usually achievable concentrations. Cettzoxime is overall similar in antibacterial activity to cefotaxime and moxalactam, Cetizoxime is not hydrolyzed by common plasmid and chromosomal @-laclamases. Serum levels of coflizoxime after intramuscular and intravenous injection are similar to those of cefotaxime and moxalactam. The halt Hfe is 1.610 1.9 hours in norma individuals. The compound isnot metabolized and is ceared trom the bady by glomerular firation, Celizoxime enters most body fuis. including the cerebrospinal id, to produce therapeutic concentrations agains clinically important bacteria. Ceflizoxime accumulates in the pres ence of ronal failure, bul ts removed from the bady by hemodialysis and pertoneal dialysis. Cetizoxime hhas proved to be an ellective chemotherapeutic agent whan used as treatment for pneumonia, urinary tract infections, osteomyelitis, septic arthritis, meningits, perilontis, gonorthea, including pericitinase- producing isolates, and gynecological infections. No major adverse reactions have been assaciated with the use of ceftizoxime and it has produced neither disulram-4ko reactions nor bleeding (Pharmacotherapy 1984;4:47-60) OUTLINE, ‘Mechanisms of Action Antibacterial Activity Beta-Lactamase Stability Synergism with Other Antibiotics Pharmacokinetics Adverse Effects Clinical Use Use in Podiatric Patients Comparative Studies Use as @ Prophylactic Agent Clinical Role of the New Cephalosporins Cephalosporin antibiotics have a remarkable reputation.‘ They are safe, reliable and effective, and surgeons and intemists have made extensive use of them since their introduction into clinical medicine in the early 1960s. However, many infectious disease experts do not consider the cephalosporins signifi- cant contributions to the physician's armamentar- “From the Departments of Medicine and Pharmacology, Col- loge ot Physicians and Surgeons of Columbia Univers New or ‘Addross reprint requests to Harold Nev, M.D. 630 West 168th Stroot, New York, NY 10032. ium. Within the last several years we have seen the introduction of a number of broad-spectrum cephalo- sporins that inhibit many aerobic and anaerobic, {gram-positive and gram-negative bacteria, ranging from group A streptococci to the beta-lactamase- producing Haemophilus influenzae, Escherichia coli and Klebsiella pneumoniae. This article attempts to put into perspective current data on one of these new drugs — ceftizoxime (Cefizox*). Ceftizoxime belongs to a class of cephalosporins that can be structurally considered aminothiazoly- ‘oxyimino cephalosporins. These compounds in- clude cettizoxime, cefotaxime, ceftriaxone and cef- menoxime and share @ commen aminothiazolyl side chain and a methoxyimino group that provides them with beta-lactamase stability (Figure 1). The com- pounds differ by the substituent on the third position of the dihydrothiazine ring. Ceftizoxime has only a hydrogen present, in contrast to the acetoxy group present in cefotaxime, the thiotetrazol-methyl group present in cefmenoxime and the more complex acid- ic-cycli¢ function present in ceftriaxone" (Figure 1). Chemical changes at the three position produce im- portant changes in antimicrobial activity and in phar- macologic properties such as drug metabolism, pro- tein binding and excretion by the kidney. * Mechanisms of Action Like penicillins and earlier cephalosporins, cefti- zoxime inhibits bacterial cell-wall synthesis, resulting in either lysis or elongation and eventual death of the 48 PHARMACOTHERAPY aahgd bese "CH -OCOCH, om ATO AD } Coons dy, CCeimenoxine Figure 1. Structural formulas of cettizoxime and other newer cephalosporins. microorganisms. The antibacterial activity of ceftizoxime has been shown to be due to a number of different factors. Its activity against gram-positive species such as Strep- tococcus pyogenes and S. pneumoniae is related to its high affinity for the penicilin-binding proteins (PBPs) of these species. Its slightly lower activity against organisms such as Staphylococcus aureus oF S. epidermidisis related to the binding to PBPs in these species, which is less than that seen with the oldest cephalosporin compounds, such as cepha- lothin, cephaloridine or cefazolin.® Similar lower ac- tivity against S. aureus is also seen with cefotaxime, cefmenoxime and ceftriaxone. However, the mini- mum inhibitory concentrations for 90% of isolates (MIC,.) are 3-4 g/ml, which are actually compara- bie to the values found for oral cephalosporins such as cephalexin and for cefoxitin, The excellent activity of ceftizoxime against gram-negative bacteria such as E. coli, Klebsiella and Proteus is related both to tts ability to pass through the outer cell envelope of the organisms and to beta-lactamase stability against the common plasmid and chromosomal beta-lacta- mases. The high affinity for critical PBPs in these species, namely PBPs 1b and 3, which are involved in septum formation and cell-wall elongation is also important Vowume 4, Numeen 2, MARCH/APRIL 1984 Antibacterial Activity ‘Table 1 gives the comparative cumulative MIC val- ues for ceftizoxime, cefotaxime and moxalactam against a variety of bacteria.” Numerous investiga- {ors have shown that 90% of S. 1es will De inhibited by <0.01 g/ml of ceftizoxime.”" Similarly, group B streptococci and S. pneumoniae wil be in- hibited by <0.2 ug/ml." S, bovis is inhibited also by =0.2 g/m. Incontrast, S. faecalisis resistant, as are some viridans streptococcal species.” All Neisseria gonorrhoeae and H. influenzae, both beta-lacta- mase-positive and -negative isolates, are inhibited by <0.03-03 ygiml.** Strains of N. meningitidis are inhibited by =0.1 ug/ml." S. aureus haas ceft- Zoxime MIC values in the range of 3 to 8 g/ml, and as with other cephalosporins, methicilin-resistant S. aureus and S. epidermidis are resistant.’ "® The MIC,, for the majority of gram-negative bacilli is <1 1xg!ml, with the exception of selected strains of En- terobacter aerogenes, E. cloacae and Citrobacter freundii2.°® These few strains are usually resistant to the other third-generation cephalosporins.” * In general, MIC,, values for ceftizoxime, cefotaxime and moxalactam differ at most by a single tube dilu- tion, and cettizoxime is more active than cefopara- zone against most bacteria except Pseudomonas. Ceftizoxime has relatively weak activity against Pseudomonas aeruginosa in contrast to compounds such as cefsulodin, cefoperazone and even moxa- lactam. The last should not be considered a first-line antipseudomonal compound.’ #5 Ceftizoxime has excellent activity against Proteus mirabilis, P. vul- garis and P. stuarti. It is slightly more active against Serratia marcescens than is cefotaxime. The sus- ceptibility of nonfermenting aerobic gram-negative species, such as Flavobacterium, Pseudomonas ce- pacia, P. maltophilia and Acinetobacter calcoaceti- cus, is extremely variable.”-®*" The antianaerobic activity of ceftizoxime has been studied by many workers. in general, its activity against anaer- obes is comparable to that of cafoxitin and cefota ime, with the exception that Bacteroides fragilis strains are more susceptible to cefoxitin than they are to ceftizoxime. Peptococci and peptostrepto- cocci are inhibited by <2 ugiml. However, some or- ganisms, such as Actinomyces and some B. ‘rags strains, require concentrations in the range of 32-64 agin, Beta-Lactamase Stability Ceftizoxime is stable to the TEM beta-lactamase, also teferred to as the Richmond-Sykes type Ma beta-lactamase; this enzyme is present in Haomo- philus, N. , E. coli, Salmonella and Shi- gella spacies.* 7 2%.°.95 The enzyme is plasmid me- diated and is the most important beta-lactamase, since it accounts for 60-70% of all beta-lactamase activity found in clinical isolates. Ceftizoxime is also stable against attack by the OXA-plasmid beta lacta- mases that are present in some E. coli strains. Cefti- Pe EVALUATION OF CEFTIZOXIME — New 49 Table 1. Comparative Cumulative MIC Values for Cettizoxime, Cefotaxime and Moxalactam ‘Cumulative Percentage of Strains Inhibited Number of oo Strains <0.125 05 1 2 4 8 16 Bacterial Species Tested ug/ml xgiml agi agiml gil ugim! g/ml Gram positive ‘Staph. aureus Cettizoxime 707 1 4 7 83 88 99100 Colotaxime 706 2 3 12 «82 9B 100100 Moxalactam 703 1 1 2 3 17 8 8B Staph. epidermidis Ceftizoxime 248, 10 48 BOA RH BD. Cefotaxime 249 3 32 54 66H Moxalactam 248 o 1 5 6 8 51 BB Strep. agalactiae ‘Seieoame 107 98 100 100 100 100100100 Cofotaxime 110 99 100 100-100 100. 100-100 Moxalactam 110 6 10 17 44 $$ 99 100 ‘Strep. faecalis Ceftizoxime 312 1 1 3 6 12 18 a8 Cefotaxime 312 4 1 3 8 12 Ww a Moxalactam 312 0 0 ° ° 1 1 3 Nonhomoiytic nongroup D ‘Streptococcus Cetizoxime 25 60 96 «= 98 = 100100100100. Cefotaxime 25 9 98 =—998 = 100 100100100 Moxalactam 25 304A 4k BD Gram negative — Aerobic Acinetobacter calcoacetious var. anitratus Cettizoxime 105 1 3 12 8 55 8D Cefotaxime 54 o 2 2 7 2% 84 8 Moxalactam 54 2 2 2 2 4 7 34 Gitrobacter diversus Ceflizoxime 42 9 959595100 Cefotaxcime 28 7% 9 9% 9% 9 96 100 Moxalactam 23 8 9 9 97 97 97 100 (Chrobacter treundit Cettizoxime at ey 86 8B www Cefotaxime 67 52 84 855 THY Moxalactam 67 6 8 8 8 88 97 100 Escherichia coll Coftizoxime 2270 9 9399 100, 100100100 Cofotaxime 19882 9 9899 8B 100100100 Moxalactam 1633, 69 98 = 98g 100S 10010, Enterobacter aerogenes Cettizoxime 148 68 78 B45 Cofotaxime 100 ey 8} 86 BF BBC 100 Maxalactam 100 “4 79 84 = 9094 8B 100 Enterobacter aggiomerans Cottizoxime at e909 SH HS Cefotaxime 19 Cs Moxalactam 18 78 94 = 49100100 Enterobacter cloacae Cettizoxime 266 S784 FTG Cetotaxime 209 3880 8G Moxalactam 206 60 8? 8884100 Kelbsiella pneumoniae Cefizoxime 599 98 98-100 00, 100100100 Cefotaxime 472 29 99-100 400100100100 Moxalactam 460 72 98 9 99 100 100 100 Morganetia morganit Ceftizoxime 79 461 Bt FF Cefotaxime 52 S487 KB Moxalactam 5t 84 9598S 100 100 100-100 Pasteurella muttocida Cetizoxime 5 100 100 100100 100 100-100 50 PHARMACOTHERAPY Table 1. (Continued) Vowume 4, Numaer 2, MarcH/APAI, 1984 ‘Cumulative Percentage of Strains inhibited Number of Swans “0125 05. 7 2. 4 8 16 Bacterial Species Tested ngiml agi —ugiml _xgiml gil gil agit Cofotexime 3 100 100 100 100. t00—St00.—«100 Moxalactam 3 6700 1 portato, e010 «100 100400 Ceftizoxime 27 9% = 99 100,100 100100100 Cefotaxime 176 9 89 = 9 100 100 100-00. Moxalactam 161 at 98888100 100 100100 Proteus vulgaris Cottizoxime 4 98 100 © 100» 109 100100100 Cetotaxime 2 55 91 = 99,100 100 t00 S100 Moxalactam 20 45 100 100 100-100 100100 Providencia rettgeri Coftzoxime 20 9 = 99 = 90100 100109100 Cefotaxime 16 5094 = 84100 100 100100, Moxalaciam 15 % 9 93 93 93 100 100 Providencia sp. Ceftizoxime ae BB HHH 100 Gefotaxime 29 5 7888038100 Moxalactam 29 a Pseudomonas aeruginosa Ceftizoxime 568 1 1 1 2 2 5 7 Cetotaxime 319 ' 2 3 4 6 2B Bt Moxalactam 37 1 1 2 8 5 B&B 7 Pseudomonas sp. Ceftizoxime 65 1 1 3 4 2h 85 Cototaxime 3t o 0 8 8 28 & 7H Moxalactam 29 0 0 7 7% 85 65 Serratia marcescens Cettizoxime 109 7 93 «949585 8H 100 Cofotaxime 87 7 7 90 tg? Moxalactarn 60 3 88 85 90H 10D Gram negative — Anaerobic Bacteroides tragis Cettizoxime n a - 0 Gefotaxime 7 = = = = = % «® Moxalactam 7 = = = = zoxime is stable against hydrolysis by most of the Richmond-Sykes chromosomal beta-lactamases, referred to as types la, Ib and Id enzymes,” ** pres- ent in species such as Enterobacter, Citrobacter and Morganella. Furthermore, ceftizoxime is not hydrolyzed by the beta-lactamase present in S. aureus. Synergism with Other Antibiotics Ceftizoxime has been shown to act synergisti- cally with aminoglycosides, such as gentamicin, tobramycin and amikacin, when tested against or- ganisms such as P. aeruginosaand against certain members of the Enterobacteriaceae family.*"-* In general, however, itis dificult to demonstrate synes- gy against Enterobacteriaveae because the com- Pound by itself is exiremely active against these genera. Combinations of ceftizoxime with the ureido- penicillins, such as aziocillin or meziocillin and with piperacillin or ticarcilin, do not show antagonism against either Enterobacteriaceae or Pseudo- monas.” Indeed, synergy or additive effectis seen in ‘approximately one-fourth of organisms. Synergy be- tween ceftizoxime and other bela-lactams is rarely seen, but in vitro test antagonism has been reported when ceftizoxime and cefoxitin are combined." Pharmacokinetics Ceftizoxime has been administered by both the intramuscular and intravenous routes to healthy adult volunteers and to individuals with renal insuffi ciency." The peak serum concentration after ad- ‘ministration of 500 mg by intramuscufar injection was. 15.2 ugimnl in a series of healthy Japanese subjects sludied by Onkawa and co-workers. Peak serum concentration in healthy subjects who were given 500 mg intramuscularly by Neu and Srinivasan were: 13.7 ngiml.® The differences in these two studies probably is related to the larger habitus of the Ameri- ‘can volunteers. At four hours, levels of 4.5 ug/ml were present, and at six hours the level was 1.6 ug/ mi, At 12 and 24 hours after a single intramuscular injection, ceftizoxime could not be detected in the serum, Pe EVALUATION OF CEFTIZOXIME ‘Neu 51 Table 2. Pharmacokinetic Values for Coftizoxime, Moxalactam, Cefotaxime and Cefoperazone Value Ceftizoxime Moxalactam Cetotaxime __Cefoperazone Protein binding (2% serum) 30 3t 35 82-08 ‘Serum haitife (hr) 19 20 1.0 20 Peak serum levels? tg im. (ug/ml) 38.0 27.0 205 650 1 giv. (agim)) 1120 94.0 101.7 153.0 6-hour serum concentration 1 gim. (ug/ml) 60 89 10, 18.0 1 giv. (ugiml) 39 60 0.00 70 ‘Major route of excretion urine by urine by Urine by tubular Bile and urine glomerular ‘glomerular secretion filtration {iltation Renal excretion (% at 8 fr) 20 7 65 20-80 % Metabolized None None 15-25 1 20-259 ‘Combined data from the pharmacotinetic studies sted in the zeference list =Peroaniage of protein binding varies withthe serum concentration Given as bolus injection,

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