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Home , Cefamandole, Cefmetazole, Cefonicid, Cefoperazone, Cefotetan, Cefpirome

gnosts.and Ivtanagenment of Infectious I)iscases

i

CHAPTER 20

Cephalosporins COO- DAVID R. ANDES A WILLIAM A. CRAIG FIGURE 20-1 . Basic nucleus .

Although the discovery of the cephalosporin class was re- duced by gram-negative anaerobic and aerobic ." These com. ported in 1945, it took nearly two decades for this class to achieve pounds, however, have lower affinity for the -binding protein clinical utility. Giuseppe Brotzu is widely credited for discovery of the (PBP) target in gram-positive bacteria .' The group is broad- inhibitory effects of sewage outflow in Sardinia, structurally related to the but originated as a metabo . Italy.' Professor Brotzu subsequently isolated the mold Cephalosporin lite from Streptomyces lactamdurans .b The basic building block of the B acremonium (now Acremonium chrysogenum) and demonstrated an- cephamycin group is cephamycin C . Hydrolysis of cephamycin C, timicrobial activity of culture filtrates against both gram-positive and however, produces the 7-ACA nucleus. gram-negative bacteria . He also demonstrated the in vivo activity of Many modifications of the acyl side chain have been undertaken . these culture filtrates in both animal models and several pa- The first compounds resulting from addition of a thienyl ring or a tients. The filtrate was used both locally by injection into skin ab- tetrazole structure at R1 included the first-generation cephalosporins, scesses and systemically for the therapy of brucella and typhoid . A decade after the initial discovery', the cephalosporin substances C were isolated and identified as fermentation products of the mold .' Investigators at Oxford, including Florey and Abraham, systematically studied the physical, chemical, and structural characteristics of N=N` S cephalosporins as they had those of the penicillin class a decade ear- N-CH2-C-HN N-N lier. Three substances, cephalosporins P, N, and C, were identified . S J_Cl~ Each of the products possessed activity. However, only CH2-S__~1 demonstrated activity against both gram-negative and NmC-CH2 -positive bacteria . In addition, it had advantageous stability in the pres- A COOH ence of acid and penicillinases .2 Cephalosporin C became the founda- tion of subsequent drug development . - The first cephalosporin, cephalothin, was introduced for clinical use 0 in 1964 . There are more than 20 cephalosporin in use today . J-CH2-C-HN S The cephalosporin class is among the most widely prescribed antimi- CH2-O-C-CH3 crobial classes because of its broad spectrum of activity, low toxicity, 11 B ease of administration, and favorable pharmacokinetic profile . COOH FlGUR G, Cefa< CHEMISTRY Cephapirin 0 Most of the available cephalosporins are semisynthetic derivatives of N S-CH2-C-HN . The basic structure of the nucleus includes a 11 cephalosporin C \\ / II - 3-lactam ring fused to a six-member sulfur-containing dihydrothiazine 0 CH,-O-C CK cephalot stitution ring (Fig. 20-1). The cephem nucleus is chemically distinct from the C oral absi penicillin nucleus, which in contrast contains a five-member thiazoli- COOH clor, cef dine ring . Basic structure numbering of the cephalosporin ring system Cephradine . The starting lated on, begins within the dihydrothiazine ring at the sulfur moiety enhance material utilized as the nucleus for current cephalosporin development D CH-C-HN pivoxyl is 7-aminocephalosporanic acid (7-ACA) . Attempts to alter the physio- CH3 are curr chemical and biologic properties of the cephalosporins by chemical side The chain modifications were based upon similar success with structural velopm, .' changes at the 6-aminopenicillanic acid side chain of penicillin COOH are due Chemical modifications of the basic cephem structure by substitution of changes constituents at positions 1, 3, and 7 have led to the various cephalosporin group tt E CH-C-HN compounds in use today.°s Alterations in positions C7 and C3 are also HO chain a commonly referred to as RI and R2, respectively. In general, changes at CH3 of impT RI affect the microbial spectrum of activity. These modifications often the q-c affect the stability of the compound to enzymatic destruction by (3-lac- COOH The se . tamases or the affinity of the compound for the drug target . Modification Cephalexin additio at R2 often alters the pharmacology of the compound . Changes in the ring at R2 constituent may influence the ability of the compound to reach cer- CH-C-HN tain infection sites such as the central nervous system or may simply F many CH prolong the elimination half-life of the drug . 0 and 2( The predominant changes at RI (position 7) include the addition of H2 Puoft an acyl side chain and the substitution of the hydrogen with a methoxy COOH group .' This RI methoxy substitution led to the development of the FIGURE 20-2. First-generation cephalosporins. A, Cefaz4 cephamycin group of compounds, such as , , and B, Cephalothin . C, Cephapirin. D, Cephradine . E, Cefadro . This alteration enhanced resistance to (3-lactamase pro- F, Cephalexin .

Cefotetan 0 I OCH3 S II 2 __1 N-N 1 CH-C- N I'll II CH-C-N N-N HO-C~~S CH2-S-~ N I I N CH2-S II OH N 0 COON CH3 E COOH CH3 Cefoxitin 0 I OCH3 ese corn. CH2 - C-N 0 g protein II I N-N group is CH-C-N I I CH2-0-C-NH2 metabo- CH2 -S N F ck of the OH k COOH nycin C, COOH CH2SO3H dertaken . ring or a CH-C-HN osporins, II I 0 -C- N I II CI II NH2 O CH2-O-C-NH2 N COON I OCH3 COON CH3 -N HO CH-C- HN Cefmetazole I 1 11 CH=CH J_CH3 II I OCH3 H NH2 0 5 N-N N-C-CH2-S -CH2- C-N COON CH2-S-~, N HO O/f D C=O CH3 CH-C-HN I II I H NH2 O CI COOH FIGURE 20-3 . Second-generation cephalosporins . A, Cefamandole . B, Cefonicid . C, Cefuroxime . D, Cefmetazole . E, Cefotetan . F, Cefoxitin . G, Cefaclor. H, Cefprozil . I, Loracarbef. 0 II -C-C cephalothin, , and cefazolin (Fig . 20-2). The simple sub- reduces activity against staphylococci . Two other modifications that stitution of an aminobenzyl group in the 7 position is important for have resulted in compounds with increased activity against P aerugi- oral absorption of the cephalosporins .5 Cephalexin, cephradine, cefa- nosa are an ureido-2,3-dioxopiperazine group and a carboxyl group on clor, cefprozil, and loracarbef all have this structure or a closely re- the a-carbon with and moxalactam, respectively .' These lated one (Fig . 20-3). Absorption of later generation cephalosporins is changes are similar to those with and . enhanced by the production of ester formulations . Axetil, proxetil, or Numerous modifications at R2 or the 3 position have also played a pivoxyl esters of cefuroxime, ceftamet, , and significant role in the development of the current cephalosporins . An 3 are currently available. acetoxy side chain is present in cephalothin, cephapirin, and cefo- The majority of the chemical modifications in cephalosporin de- taxime.5 Cephalosporins with this structure can be metabolized in both velopment, which have resulted in changes in microbiologic spectrum, the serum and liver to a less active desacetyl derivative . Such drugs are due to alterations at the a-carbon of the acyl side chain .' These also tend to have a short half-life . A chloride substitution at R2 en- changes have ranged from the relatively simple addition of a hydroxyl hanced the gram-negative spectrum of activity and led to the develop- group to the addition of large synthetic moieties . Each of the acyl side ment of cefaclor, an early second-generation cephalosporin. The chain alterations has led to enhanced gram-negative potency because unique pharmacology of results from an R2 modification . 3 of improved (3-lactamase stability. The addition of a hydroxyl group at Substitution of a heterocyclic thiomethyl group at the 3 position in- the 01-carbon led to the second-generation cephalosporin cefamandole . creases its biliary secretion and remarkably prolongs the elimination The second-generation cephalosporin cefuroxime resulted from the half-life of the compound because of protein binding .'," The addition addition of a methoxyimino group in the a position along with a furyl of positively charged quaternary ammonium moieties in the 3 position nng at the P-acyl side chain . Addition of a 2-aminothiazol group to the contributed to the development of the fourth-generation cephalo- 7- Q-acyl side chain and a methoxyimino group to the a-carbon led to sporins and .9 The chemical modification produces 3 many of the third- and fourth-generation cephalosporins (Figs . 20-4 a zwitterion, which enhances the ability of the compound to penetrate and 20-5)."9 , , ceftriaxone, cefepime, cef- the outer membrane of gram-negative organisms . Not all modifica- p>rome, and cefpodoxime all have a similar structure at the 7 position . tions have led to desired effects . The placement of a thiomethyl tetra- ;efazolin . differs from these drugs by replacing the methoxyimino zole ring (MTT) at the R2 position not only enhanced antibacterial efadroxil- group with a dimethylacetic acid moiety attached to the imino group .' activity but also resulted in two important adverse effects that have s alteration enhances activity against aeruginosa but limited use of these compounds ."," Cefamandole, cefotetan, and

eDin'n js-mna'M•inancment of Infectious Diseases -

Cefoperazone Moxalactam CH3 1 HO-CH-C-N N-N O H O 11 1 11 1 NH CH2-S N HO CH-C-N N' CI =O I I H2N ( N` '_O COOH CH3

A A N~O I C2H5 Cefoperazone 0 H II I HO-CH-C-N H2N I NH I C=O B I I C N_1~O COOH CH3 FIGUF B, Cefp; • N/~O Ceftazidime 1 0 H cepham C2H5 II 1 N C-C-N ative an group h NI CH 2 Howeve against group, rately ft COOH C widest Ceftizoxime fepime 0 H bacilli II I gram-p' N are alsi C-C-N Cefpodoxime i N MRSA- group c S D H2N II I OCH3 CH-C-N COOH MECH • NI Ceftriaxone H2N17\S The me II I S OCH3 COOH that of N C-C-N ing wit J Ceftbuten OH compok NI H2NJ! S 9 ~ N-N structur OCH3 II I ternatin COOH CH-C-N CH3 • The po II chain o E N\ H2N S O- These s OCH2000H COOH K

FIGURE 20-4. Third-generation cephalosporins . A, Cefoperazone. B, Cefotaxime. C, Ceftazidime . D, Ceftizoxime . E, Moxalactam. G, . H, Cefditoren . I, . J, Cefpodoxime. K, .

cefoperazone contain this MTT side chain, which is responsible for CLASSIFICATION coagulation abnormalities related to antagonism of action . This side chain is also responsible for the -like properties of There are several microbiologic and pharmacologic difference these compounds . could serve as a basis for classification in the cephalosporin drug c More recently, cephalosporins with enhanced activity against me- The most widely accepted classification includes four divisio thicillin-resistant aureus (MRSA) have been devel- generations based loosely on the microbial spectrum of activity oped. A variety of structural alterations at the 3 and 7 positions have 20-1) . The first-generation cephalosporins exhibit activity focus increased stability to R-lactamase inactivation and increased binding manly on gram-positive bacteria. The second-generation drugs to the altered PBP 2a' . 13-15 Because some of these compounds require enhanced activity against gram-negative bacilli but maintain v more lipophilicity at the 3 position for activity, prodrugs have been re- degrees of activity against gram-positive cocci . The cephamycin 16 quired to enhance aqueous solubility . is included in the second-generation classification . as well'

Cefepime cytoplasm by the action of a group of that includes transpep- tidases, carboxypeptidases, and endopeptidases. The lactam ring pro- vides for and cephalosporins a conformation similar to the terminal D-alanine-D-alanine of the pentapeptide .'s These antibiotics bind covalently to these enzymes, in particular the transpeptidases, re- sulting in the loss of activity .19 The enzyme drug targets are 9,2o CH -N+-1) referred to as PBPs .' 2 The location of the PBPs relative to the extracellular space dif- COOH fers between gram-positive and gram-negative bacteria . The pepti- CH3 doglycan of gram-positive bacteria is located on the outer surface of CH3 A Cefpirome the cell. A complex lipopolysaccharide structure is located on the NH 2 outermost surface of gram-negative bacteria . Cephalosporins must 0 H first penetrate or diffuse across the lipopolysaccharide membrane to II I reach the PBPs of gram-negative bacteria . The PBP targets within H-C-N bacteria vary by type and amount . These targets are numbered by ),1 1 II . Letters differentiate N convention on the basis of molecular weight H2N proteins of similar molecular weight . Gram-positive and gram- S "I OCH3 COOH negative cocci typically have 3 to 5 PBPs ; gram-negative bacilli usually contain 7 to 10 PBPs . The cephalosporin drugs can vary in B affinity for each of these drug targets . At low concentrations, cephalosporins preferentially bind to PBP 3 in gram-negative . Fourth-generation cephalosporins . A, Cefepime . .N FIGURE 20-5 bacilli, resulting in filament formation with septa ." The events fol- B, Cefpirome . lowing the covalent binding of cephalosporins to the PBP targets that lead to cell lysis and death are not entirely understood . are noted for their additional activity against gram-neg- In general, cephalosporins are considered bactericidal drugs . ative anaerobic bacteria, such as Bacteroides spp. The third-generation The rate of killing of bacteria by cephalosporins exhibits minimal group has markedly increased potency against gram-negative bacilli . dependence on the concentration of the antibiotic ." Maximal bac- However, for some compounds in the third-generation class, activity terial killing is observed at concentrations four times the minimal against gram-positive cocci is reduced . Among the third-generation inhibitory concentration (MIC) . Cephalosporins produce persis- group, a few compounds, such as ceftazidime, are considered sepa- tent suppression of bacterial growth (i .e., the postantibiotic effect) rately for activity against P aeruginosa. The fourth generation has the of several hours' duration with gram-positive bacteria but induce widest spectrum of activity of the groups . These drugs, such as ce- very short or no postantibiotic effects with gram-negative fepime and cefpirome, have activity against most gram-negative bacilli .23 • 2 4 The duration of time that the drug concentrations ex- bacilli including P. aeruginosa and maintain their potency against ceed the MIC is the major determinant of the antibacterial activity gram-positive cocci. The third- and fourth-generation drugs combined of the cephalosporins .24,25 are also called the extended-spectrum cephalosporins . When the MRSA-active cephalosporins are approved for clinical use, a fifth SPECTRUM OF ACTIVITY group or generation will need to be created . The cephalosporins are active against a wide variety of aerobic and 26-55 MECHANISM OF ACTION anaerobic bacteria (Tables 20-2 and 20-3) . Most drugs are active against streptococci and staphylococci . Some of the differences in po- -OCH3 The mechanism of antibacterial activity of cephalosporins is similar to tency among the agents are magnified by their activity against peni- that of other l3-lactam drugs. Bacterial growth is inhibited by interfer- cillin-resistant pneumococci . Cefditoren, ceftriaxone, cefotaxime, ce- ing with the synthesis of the . The primary target of these fepime, and cefpirome have the greatest potency against those compounds within the cell wall is the cross-linkage organisms . The cephamycins, ceftazidime, cefixime, and ceftibuten structure ." are polysaccharide chains consisting of al- have the poorest activity against -susceptible staphylococci . ternating N-acetylglucosamine and N-acetylmuramic acid residues . Although methicillin-resistant staphylococci are resistant to all the The polysaccharide chains are cross-linked at the pentapeptide side current cephalosporins, the new MRSA cephalosporins exhibit MICs chain of the N-acetylmuramic acid residues to form a netlike structure . of about 1 to 4 g/mL with such strains ."," Enterococci have also con- These structures are inserted into the cytoplasmic membrane from the sistently been resistant to the cephalosporins with most MICs greater

Icon . F, FfstGeneration Second Generation ('epham,veins Third Generation Fourth Generaon Parenteral Cefazolin Cefamandole (Mandol) Cefmetazole (Zefazone) Cefoperazone (Cefobid) Cefepime (Maxipime) (Ancef, Kefzol) Cephalothin (Keflin, Seffin) Cefonicid (Monocid) Cefotetan (Cefotan) Cefotaxime (Claforan) Cefpirome Cephapirin (Cefadyl) Cefuroxime Cefoxitin (Mefoxin) Ceftazidime (Fortaz) (Kefurox, Zinacef) -rences that Cephradine (Velosef) Ceftizoxime (Cefizox) i • Ceftriaxone (Rocephin) livisions a Moxalactam ivity (Table Cefadroxil (Duricef, Ultracef) Cefaclor (Ceclor) Cefdinir (Omnicef) focused P6- Cephalexin (Keflex, Biocef, Cefprozil (Cefzil) Cefditoren (Spectracef) drugs ha" Keftab) ,in varyln Cephradine (Veloset) Cefuroxime-axetil (Ceftin) Cefixime (Suprax) Loracarbef (Lorabid) Cefpodoxime (Vantin) nycin grc1P Ceftibuten (Cedax) well. Tip Streptococcus Viridans Staphylococcus pneumoniae Streptococcus Streptococcus Streptococci aureus Staphylococcus Haemophilus Moraxella Neisseria (PSSP) (PRSP) pyogenes agalactiae Group (MSSA) epidermidis infiuenzae catarrhalis meningitidis gonorrhoeae

First Generation Cefazolin 0 .5/4 32/>32 0.12/0.12 0.12/0.12 0 .12/0 .12 0 .5/2 0.5/>32 4/16 2/4 - 16/32 Cephalothin 0 .12/0 .25 8/16 0.05/0.10 0 .12/0.5 0 .25/0 .50 0 .12/0 .5 0.5/32 4/8 4/8 0.25/0.5 8/32 Cefadroxil (0) 2/4 >32 0.12/0 .25 0 .25/2 2/8 4/>32 16/>32 2/4 8/64 Cephalexin (0) 1/2 >32 0.25/2 0 .5/4 2/4 1/>32 8/16 2/8 2/2 4/16 Cephradine (0) 2/4 >32 0.25/2 0 .5/2 1/4 4/>32 4/16 2/4 8/16 Second Generation Cefamandole 0 .12/0 .5 8/>32 0.12/0 .12 0 .12/0 .5 0.12/4 1/1 0 .5/>32 2/8 1/4 0.12/0 .12 0.25/4 Cefonicid 0 .5/1 4/>32 0.12/0 .12 0 .12/2 0.12/8 1/2 2/>32 0 .5/1 1/4 0.12/2 0.06/0.5 Cefuroxime 0 .12/0 .25 4/>32 0 .12/0 .12 0 .12/0 .12 0.12/0.5 1/2 0 .5/>32 1/2 0.5/2 0 .12/2 0.015/0 .25 Cefaclor (0) 0 .5/1 16/>32 0 .06/0 .5 0 .5/2 - 1/8 1/>32 2/32 0.5/2 0 .06/0 .25 0.25/16 Cefprozil (0) 0 .12/0 .5 8/>32 0 .03/0 .12 0 .06/0 .25 0 .5/2 0 .25/32 2/16 1/8 - 0.12/4 Loracarbef (0) 0 .5/2 >32 0 .5/2 0 .5/2 1/4 4/>32 1/4 0.5/4 0 .12/0 .25 0.5/4 Cephamycins Cefmetazole 2/16 >32 0 .5/0 .5 2/2 2/4 4/16 8/>32 1/4 0.12/0.5 0 .12/0 .12 0 .25/4 Cefotetan 8/16 >32 2/4 4/8 2/8 8/16 32/>32 1/2 0.12/2 0 .12/0.25 0 .25/2 Cefoxitin 2/4 32/>32 1/2 2/2 4/16 4/8 2/>32 1/4 0.25/0 .5 0 .12/0.25 0 .25/4 Third Generation Cefoperazone 0.06/0.12 4/16 0 .12/0.12 0.12/0.25 0 .5/1 2/4 2/>32 0 .015/0.25 0 .12/2 0.12/0.5 0 .03/0 .06 Cefotaxime 0.015/0.06 0.5/2 0 .015/0 .015 0.03/0.25 0 .06/0 .25 2/2 4/>32 0 .008/0.015 0 .5/1 0.004/0.008 0 .004/0 .008 Ceftazidime 0 .25/1 16/>32 0 .12/0.25 0.25/0.5 1/2 8/32 8/>32 0 .06/0 .12 0 .03/0 .5 0.015/0.06 0 .03/0.06 Ceftizoxime 0.25/1 16/32 0 .015/0 .015 0.12/0.12 0 .25/2 4/8 4/>32 0 .015/0.03 0 .03/0 .5 0 .008/0.03 0 .008/0 .015 Ceftriaxone 0.03/0.06 0.5/2 0.015/0 .03 0.03/0.06 0 .06/0 .25 2/4 4/>32 0 .008/0.015 0 .25/0 .5 0 .008/0.015 0 .002/0 .004 Moxalactarn 1/1 - 1/2 - - 8/16 8/>32 0 .03/0 .12 0 .03/0 .12 0 .008/0.06 0.015/0 .06 Cefdinir (0) 0 .06/0 .12 2/8 0.015/0 .03 0 .03/0 .06 0.25/0.5 0 .25/>32 0 .12/0 .5 0 .06/0.25 0 .06/0 .25 0.008/0 .06 Cefditoren (0) 0 .015/0 .03 0.5/2 0.008/0 .015 0 .06/1 0.25/1 0 .25/>32 0 .008/0 .015 0 .25/1 <0 .06/0 .06 0.004/0 .06 Cefixime (0) 0 .25/1 32/>32 0.06/0.25 0 .12/0 .25 16/>32 16/>32 0 .015/0 .12 0 .03/0.5 <0 .06/0 .06 0.015/0 .06 Cefpodoxime (0) 0 .015/0 .06 2/>32 0.06/0.12 0 .03/0 .12 - 2/4 2/>32 0.015/0 .12 1/2 <0 .06/0.06 0 .06/0 .06 Ceftibuten (0) 4/8 >32 0.5/2 4/16 - 16/>32 16/>32 - 0.06/0 .12 2/4 0 .06/0.25 0 .015/0.5 Fourth Generation Cefepime 0 .06/0 .12 0.5/2 0 .015/0.12 0 .05/0 .05 0.016/0 .03 2/4 2/>32 0.06/0.12 1/4 0.03/0 .06 0 .03/0 .06 Cefpirome 0 .03/0 .12 0.5/2 0 .008/0.06 .06/.06 0.06/0.25 1/2 1/>32 0.06/0.12 0 .5/2 0.06/0 .06 0 .015/0 .12

MSSA, methicillin-susceptible S . aureus ; (0), oral ; PRSP, penicillin-resistant S . pneumoniae ; PSSP, penicillin-susceptible S. pneumoniae .

Eseherichia Xlebsiella - Enterobacter C'itrobacter Pceudomonac Morganella Hactero C halo, tins coil pneumoniae mirabilic aerogenes cloacae freundii aeruginosa- cp- fra

First Generation Cefazolin 2/16 2/>16 4/16 >32 >32 >32 >32 >32 >32 >32 2/4 2/8 Cephalothin 4/8 1/16 8/16 >32 >32 >32 >32 >32 >32 >32 2/4 4/8 Cefadroxil (O) 4/>16 8/>16 16/>32 " >32 >32 >32 >32 >32 >32 >32 8/> 16 4/16 Cephalexin (0) 8/>16 8/32 16/>32 >32 >32 >32 >32 >32 >32 >32 4/16 8/> 16 Cephradine (0) 4/>16 4/>16 16/>32 >32 >32 >32 >32 >32 >32 >32 4/> 16 8/> 16 Second Generation Cefamandole 1/2 1/8 1/2 4/>32 2/>32 2/>32 16/>32 >32 4/>32 32/>32 0 .5/4 0.5/2 Cefonicid 2/8 2/8 1/2 4/>32 8/>32 8/>32 >32 >32 16/>32 32/>32 2/8 2/8 Cefuroxime 2/8 2/16 2/4 8/>32 8/>32 8/>32 >32 >32 32/>32 8/>32 4/8 2/4 Cefaclor (0) 2/>16 2/32 2/4 >32 >32 >32 >32 >32 >32 >32 2/8 4/16 Cefprozil (0) 2/8 1/>32 2/2 >32 >32 16/>32 16/>32 >32 16/> 32 >32 2/8 4/16 Loracarbef (0) 1/>16 0 .5/8 0.5/2 16/>32 16/>32 4/>32 >32 >32 32/>32 >32 0.5/8 0.25/8 Cephamycins Cefmetazole 0 .5/1 1/2 2/4 >32 >32 >32 16/>32 >32 4/8 8/>32 0.5/2 1/2 Cefotetan 0.12/0 .5 0.12/0.5 0.12/0.5 32/>32 8/>32 0 .5/>32 1/8 >32 2/4 8/>32 0 .12/0.12 0 .12/0.5 Cefoxitin 2/8 2/8 2/4 >32 >32 >32 16/>32 >32 8/16 8/32 2/4 2/4 Third Generation Cefoperazone 0.12/8 0.25/8 0 .5/1 0.25/8 0.25/8 0 .5/32 2/8 4/>32 1/8 32/>32 0.5/4 0.25/1 Cefotaxime 0 .06/0 .25 0 .06/0 .25 0.06/0 .25 0.12/16 0.25/32 0.25/>32 0.25/2 16/>32 0 .25/4 8/>32 0.06/0.12 0.06/0 .25 Ceftazidime 0 .06/0 .25 0.25/1 0.06/0 .5 0.25/32 0.25/32 0.5/>32 0.25/2 2/16 0.12/0 .5 >32 0 .12/0.5 0.06/0.25 Ceftizoxime 0 .03/0.12 0 .03/0 .12 0 .008/0 .015 0.06/16 0.06/16 '0.25/>32 0 .12/0 .5 32/>32 0 .25/2 16/>32 0.015/0.25 0.008/0.25 Ceftriaxone 0 .06/0.12 0 .06/0 .25 0 .008/0 .03 0.25/16 0.25/>32 0.12/>32 0 .25/4 32/>32 0.008/0.25 8/>32 0.06/0.25 0.03/0 .12 Moxalactam 0 .12/0.25 0 .12/0 .25 0 .25/0 .5 0.25/16 0.5/8 0.25/8 0 .25/4 32/>32 0.25/0.5 2/32 0.12/0.25 0 .12/0 .25 Cefdinir (0) 0 .12/0.25 0 .06/0.25 0 .06/0 .12 0.5/>32 0.5/>32 0.25/>32 4/32 16/>32 4/16 16/ >32 0.12/0.25 0.25/0.5 Cefditoren (0) 0 .25/0.5 0 .25/1 0.12/1 0.5/>32 1/>32 1/>32 2/32 >32 - 4/>32 0.25/0/5 0.25/0.5 Cefixime (0) 0 .12/0.25 0 .03/0.12 0.008/0 .03 0.5/>32 0.12/>32 2/>32 2/>32 >32 2/32 16/>32 0.06/0 .25 0.25/0.5 Cefpodoxime (0) 0 .25/1 0 .5/2 0 .06/0 .12 2/>32 4/>32 2/>32 1/8 >32 2/>32 16/>32 0.5/1 0 .12/0 .25 Ceftibuten (0) 0.12/0.25 0.06/0.25 0.015/0 .03 1/32 2/>32 1/>32 0 .5/8 >32 0.25/8 16/>32 0 .06/0 .25 0 .06/0 .25 Fourth Generation Cefepime 0.03/0.06 0.03/0.25 0 .06/0.12 0 .06/0.5 0 .0612 0 .06/2 0.12/0.5 2/16 0 .03/0 .12 >32 0 .06/0.12 0.03/0.06 Cefpirome 0.06/0.12 0.06/0.25 0 .06/0.12 0 .06/0.5 0 .12/4 0 .03/2 0.25/2 2/16 0 .03/0 .12 32/>32 0.06/0.25 0.06/0.12

(0), oral. Diagposrs and Islanagem4-nt of Infectious Diseascs

The number of unique f3-lactamases is markedly increasing .'] than 32 µg/mL . However, the new MRSA-active cephalosporins have Streptoc much lower MICs for -susceptible strains. These have proteases may be genetically encoded chromosomally or extrachro, .56,57 mosomally. Stable derepression of a chromosomal mutation is the fluenzae ranged from 0 .12 to 4 g/mL for most of these drugs PBP tar, The first-generation cephalosporins are not very active against most common genotypic scenario . This is observed predominantly m species, Serratia species, freundii, Nearly 4 and . In comparison, Enterobacter and , P. aeruginosa 67 The Bush type 1 AmpC cephalosporinase is capable the pne the second-generation drugs are about fourfold more potent against p2 of inactivating almost all current cephalosporins including the other these respiratory pathogens . The third-generation cephalosporins have quences cephamycins . Emergence of this type of resistance is frequent when the lowest MICs for H. influenzae and M. catarrhalis, which are 10 to ity PBP resulting from these organisms are treated only with broad 100 times lower than those of the second-generation drugs . The first- . to repre: spectrum cephalosporins.67-69 Extrachromosomal propagation is most generation cephalosporins are also not as active against Neisseria latorY rt species as the second-, third-, and fourth-generation drugs . often through plasmids but can occur through transposons . Some of Although all of the cephalosporins are considered active against these newer enzymes represent variants of the common plasmid, PHARA , , and , the encoded TEM-1, TEM-2, and SHV 1 f3-lactamases . These enzymes have been observed most commonly in K. pneumoniae and E potency of the third- and fourth-generations drugs is 10- to 100-fold . coli and The pha greater than that of the first- and second-generation cephalosporins . are referred to as extended-spectrum (3-lactamases (ESBLs) because Table 2( The increased potency of the later generation drugs extends to they are capable of inactivating many third- and fourth-generation Within i strains of Enterobacter, Serratia, Citrobacter, and Morganella cephalosporins .70-71 These enzymes are the result of amino acid substi- there ar species, which are usually resistant to the first- and second-genera- tutions related to point mutations in the common (3-lactamase genes generate tion drugs . Several cephalosporins, such as ceftazidime, cefopera- (i.e., TEM- and SHV-) . SHV ESBLs are the most common ESBU zone, ceftizoxime, cefepime, and cefpirome, are active against found in K. pneumoniae .72 Other newer plasmid f3-lactamases include most strains of P aeruginosa . The third- and fourth-generation variants of the chromosomal AmpC f3-lactamase .' These enzymes cephalosporins also exhibit enhanced potency against strains of have also been observed primarily -in K. pneumoniae and E. coli. Salmonella and Shigella . The different f3-lactamase enzymes can vary significantly in their Many cephalosporins are active against penicillin-susceptible affinity for drugs within the cephalosporin class . For example gram-positive anaerobes, such as peptostreptococci .58.59 Against cefepime and cefpirome are less susceptible than other cephalosporins , drugs such as the cephamycins, cefotaxime, cef- to inactivation by Bush type 1 ,. AmpC cephalosporinases .'^?' triaxone, and ceftizoxime have the best activity. Many of the drugs are Cephalothin, cefamandole, and cefoperazone are most susceptible to active against spirochetes including the agents of Lyme disease and inactivation by the common plasmid-encoded TEM-1, TEM-2, and .60.61 As a group, the cephalosporins have very poor activity SHV-1 (3-lactamases67'68 The cephamycins are not susceptible to inac- against , , and species .62-64 tivation by ESBLs. Ceftazidime and cefpodoxime generally exhibit •7 ce- high sensitivity to inactivation by ESBLs .70 6 On the other hand, Fusr MECHANISMS OF RESISTANCE fepime, cefpirome, and even cefotaxime and ceftriaxone may exhibit Cefa only modest inactivation and still be considered susceptible by stan- Ceph dard susceptibility testing . Tests using ceftazidime, cefpodoxime, and Ceph Four general mechanisms can result in resistance to cephalosporin Ceph antibiotics : (1) antibiotic destruction by hydrolyzing f3-lactamase cefotaxime or ceftriaxone, or both, to identify strains of K pneumo- Seca enzymes, (2) reduced penetration of the antibiotic through the niae and E. coli producing ESBLs have been devised for clinical lalt Cefa, lipopolysaccharide membrane to the PBP target, (3) enhanced ef- oratories by the National Committee for Clinical Laboratory Cefo flux of the drug from the periplasmic space, and (4) alteration in the Standards." Their recommendation is that all such strains should be Cefu PBP target resulting in reduced binding affinity. Most often resis- called resistant to cephalosporins other than the cephamycins even it Ceps ." A large prosper° Cefrr tance in a bacterial population is due to a single mechanism ; how- they are susceptible on standard susceptibility tests Cek ever, an increasing percentage of organisms are exhibiting multiple tive observational study of patients with Klebsiella bacteremia Q Cefo .6s mechanisms served a significantly poorer outcome in patients treated with third' Thin Production of f3-lactamase enzymes that hydrolyze the f3-lactam and fourth-generation cephalosporins than with .78 1 Cefo ring is a predominant resistance mechanism for many gram-nega- poorer outcome was observed primarily in strains with MICs greatgf tive bacteria . With staphylococci, most cephalosporins, with the ex- than 2 µg/mL. Thus, strains with ESBLs that have low MICs are stl, Cefo t Cdr: ception of cephaloridine, are poorly hydrolyzed by staphylococcal probably treatable with cephalosporins . Identification of ESBLs in t Celt' penicillinases. Resistance to cephalosporins in these organisms is clinical laboratory is also complicated by new emerging ESBLs call, Cd! due almost entirely to reduced binding affinity of the PBPs . the CTX-M enzymes, which hydrolyze ceftazidime much less Although all gram-negative bacilli produce (3-lactamase enzymes, other third- and fourth-generation cephalosporins and exhibit susc the type and amount of enzyme vary among organisms . These en- tibility to ceftazidime in standard susceptibility testing .",',' zymes are located in the periplasmic space between the outer It is unlikely that deletion or mutation of porin proteins causes lipopolysaccharide membrane and the inner cell membrane. Drugs mary resistance to cephalosporins. However, such changes can that are able to penetrate the outer membrane can be degraded be- the relationship between the concentrations of drug and f3-lac fore reaching the PBP target . The net antimicrobial activity of in the periplasmic space resulting in much more hydrolysis 0 cephalosporins against gram-negative bacilli is dependent upon the cephalosporin . For example, strains of K. pneumoniae con rate of penetration across the outer membrane and the stability of ESBLs have been shown to be resistant to cephamycins because the drug to the various hydrolyzing f3-lactamases. The penetration lack of an outer-membrane porin protein ." Porin-deficient strain of drugs across the outer membrane is through water-filled channels especially high in Enterobacter aerogenes .62 formed by various membrane proteins, termed porins . Movement The endogenous AcrAB multidrug efflux system in E. colt through porin channels is dependent upon the size, shape, charge, the potency of penicillins but has little effect on the activr and hydrophilic properties of the compound . The concentration of a cephalosporins .83 However, the MexAB-OprM efflux pun' drug with a slow rate of penetration is low relative to the amount of P aeruginosa has been associated with resistance to both third ° 3-lactamase within the periplasmic space . The relatively high f3-lactamase fourth-generation drugs .8 ,85 The difference between these organ concentration can enhance antibiotic inactivation. For a drug that in the impact of somewhat similar pumps is probably due can penetrate rapidly, the converse is true . For example, the zwitte- markedly higher outer-membrane permeability in E . coli th rion of cefepime enhances movement across the membrane, result- P aeruginosa.s6 ing in high concentrations in the periplasmic space and a relative net Changes in the PBP target are responsible for re resistance to drug hydrolysis .66 cephalosporin affinity and subsequent drug resistant

. The parenteral formulations are available for both intravenous ncreasing. us pneumoniae, methicillin-resistant S. aureus, H. in- only . All of the parenteral formulations Ily or extrac d some strains . Changes in the and intramuscular administration mutation is may result from amino acid substitutions or insertions . with the exception of cephradine are stable in solution at room tem- 1 wedominamay amino acid asubstitutions in PBP 2b have been described in perature for 24 hours or longer.' 6 • " Drug stability at room tempera- ,r _rcutrdii,/' Resistance in . pneumoniae and several ture facilitates use of these compounds for home intravenous therapy Np~Vhnococcus, . S rinase is cap N gtitogens has also resulted from insertion of resistance se- including continuous infusions. Many of the parenteral compounds Ae , p s including t quences1from other related species. For example, the reduced affrn- can also be administered by the intraperitoneal route for therapy of is frequent w . aureus responsible for methicillin resistance is thought peritoneal infections associated with continuous ambulatory peri- ity PBP rin S only with bro to represent a fusion product of an E. coli PBP region and the regu- toneal dialysis ."' Formulations of the oral cephalosporins are avail- pagation is lato1y iegion of the staphylococcal (3-lactamase sequence ." able as tablets or capsules and as suspensions . posons . Some In contrast to many other (3-lactams, oral preparations of the rmmon plastm cephalosporins are stable in the acid milieu of the upper gastrointesti- p PROPERTIES These enzy HARMACOLOGIC nal tract . Cephalosporins can be actively absorbed if their structure e and E. roll The pharmacologic properties of selected cephalosporins are listed in mediates transport by the di- and tripeptide transport systems in the ESBLs) bee Cephalosporins are polar, water-soluble compounds . brush border membrane in the small intestine."' Cephalexin, cephra- Table 20-490-15 'ounh-generati Within each of the first-, second-, and third-generation classifications dine, cefadroxil, cefaclor, cefprozil, and loracarbef have an aminoben- iiino acid substl. there are both oral and parenteral formulations . The only fourth- zyl group or a similar group in the 7 position and have high oral lactamase gees generation compounds in clinical use are available for parenteral use bioavailability (80% to 95%). Ceftibuten, cefixime, and cefdinir have comnwn ESB4 aanrases include 'these enzymes and E. coli . iificantly in their For examplq ,r cell h a losporins Stahility at ospori nases .7d.n Peak Cerebrospinal Cerebra- Room ~st susceptiblea Serum Fluid spinal Temperature Corwentralion Fluid .(hr) or Oral -1 . TEM-2, and cancers- trarion Half--life Range Penetration allability sceptible to inac. ('tq/rnl)' flu) (sgfmL) (%) ~ ) teneraily exhibit other hand, ce . F7rrst Generation one may exhibit Cefazolin 0.5-1 g q8h 193 (1 g) 1.9 74-86 R (65-100%) <0.7 0-4 24 -eptible by stao- Cephalothin 0.5-2 g q4-6h 64 (1 g) 0.5-1 .0 50-80 R (50-70%) 0.16-0 .31 1 24 efpodo .xime, and Cephapirm 0.5-2 g q4-6h 70 (1 g) 0.6 50-60 R (60-85%) NA NA 24 0.5-1 g q6h 50(1 g) 0.7 8-17 R (75-100%) NA NA 2-10 s of K . pneumo- Cephradine for clinical Ik Second Generation 0.7-1 .3 50-78 R (80%) 0.35-7 .4 0-8 .6 24 cal Laboratory Cefamandole 0.5-2 g q6h 88 (1 g) Cefonicid 0.5-1 g q24h 221 (1 g) 4.4 98 R (95%) NA NA 24 drains shouldbe Cefuroxime 0.75-1 .5 g q8h 39 (1 g) 1.2-1 .8 33-50 R (70-100%) 0.35-22.5 11 .6-13 .7 24 amycins even if Cephamycins A large prosper Cefmetazole 2 g q8h 143 (2 g) 1.3-1 .8 68 R (75-85%) NA NA 24 R (80%) 1.1-4 .8 0.8-3.6 24 bacteremia otr Cefotetan 1-2 g gl2h 158 (2 g) 3.5 76-90 Cefoxitin 1-2 g q6h 110 (1 g) 0.8-1 41-79 R (90%) 1.2-22 0.8-35 24 ated with third Third Generation iapenems .'s The Cefoperazone 1-3 g q8-12h 153 (1 g) 1.6-2 .1 90 H (80%) <0 .8-119 2.5-5 .9 12 th AIICs greater R (20%) rv MICs are stil Cefotaxime 1-2 g gl2h 102 (1 g) 1-1 .2 35-40 R (50-80%) 1-83 4-55 24 of ESBLs in the Ceftazidime 1-2 g q8-12h 107 (1 g) 1-2 17 R (80-90%) 1.4-30 14-45 24 24 ig called Ceftizoxime 1-2 g q6-12h 113 (1 g) 1.4-1 .7 31 R (70-100%) <0 .5-29 3-22 .6 ES BLs Ceftriaxone 1-2 g q17-24h 145(1 g) 6.4 85-95 R (50%) 2-20 1.5-7 72 much less than H (40%) exhibit suscep Moxalactam 1-2 g q8h 70(1 g) 2.2 50 R (67-88%) 0.8-39 12-69 24 Fourth Generation eins causes Pr" Cefepime 1-2 g gl2h 79(l g) 16-19 R (85%) 5.7 11 .8 24 anges can alter Cefpirome 1-2 g gl2h 80 (1 g) 10 R (90%) 0.8-4 .2 5-67% 24 nd /3-lactamase Oral--First Generation drolvsis of the Cefadroxil 0.5-1 g ql2h 15 (0 .5 g) 1.3-1 .6 20 R (90%) NA NA 80% Cephalxin R (80-100%) NA 90% rice containing 0.5-1 g q6h 5.8 (250 mg) 0.5-1 .2 6-15 NA Cephradine 0.5-1g q6h 15 (0 .5 g) 1-2 10-20 R (80-90%) NA NA 95% because of the Oral-Second Generation Gent strains are Cefaclor 250-500 mg q8h' 6 (250 mg) 0.5-1 25-50 R (50-80%) NA NA 50-90% FE 375 mg ql2h 19.2 (400 mg) s E. (ol i affects Cefprozil 500 mg ql2h 9.3 (500 mg) 1.3 35-45 R (61%) NA NA 95% the activity of Ceftroxime (axetil) 250-500 mg ql2h 4.6 (250 mg) 1.2 33-50 R (66-100%) NA NA 52-68% FE Loracarbef flux pump i° 200-400 mg gl2h 8 (200 mg) 1.0 25 R (87%) NA NA 90% hoth third- and Or'al-Third Generation Cefdinir tese organism s 300 mg gl2h 2.9 1.5-1 .7 60-73 R (18%) NA NA 25% Cefditoren (pivoxil) 200-400 mg ql2h 2.5 (200 mg) 0.8-1 .6 88 R (16-22%) NA NA 17% FE ably clue to , Cefixime 200-400 mg q12- 2.8 (200 mg)- 3-4 65-70 R (50%) NA NA 40-50% coli than in 24h 4.5 (400 mg) H (5%) Cefpw o e (proxetil) 200 mg g12h 2.2 (200 mg) 2.2-2 .7 18-40 R (29-33%) NA NA 50-80% FE Ceftibuxi 400 mg q24h 15 (400 mg) 2.4 65-77 R (57%) NA NA 75-90%

FE, food enhances; H, hepatic ; NA, not applicable; R, renal .

,the`Diagnosis and Management of Infectious Diseases

122 other groups in the 7 position and exhibit more variable bioavailabil- similar to those in serum. The cephalosporins have relatively p oor this traps ity after oral dosing . Absorption by the di- and tripeptide transport sys- intracellular concentrations . Tissue homogenates, which mix intracel- inflamm tems appears to be both pH and calcium dependent . I" Drugs that have lular and extracellular fluid, always provide concentrations that are by active low oral bioavailability can be esterified to enhance absorption . The lower than serum because of dilution by the larger intracellular V(I- Few ester prodrug is hydrolyzed after absorption in the intestinal epithelial ume . 121 This group of compounds does not achieve intracellular con lized. T cells . The esters commonly used include axetil, proxetil, and pivoxil centrations adequate for therapy for most intracellular pathogens such cephapir 23 formulations . 120 Ester prodrug formulations exist for cefuroxime, as Legionella spp .' chain in cefditoren, and cefpodoxime . Absorption of the ester is still not com- In the absence of infection, drug concentrations in the cerebrospinal modest r plete . In fact, the percent oral bioavailability of ester formulations is fluid (CSF) and the vitreous humor are low . None of the oral cefotaxir lower than that of most nonesterified compounds . Absorption of the cephalosporins achieve therapeutic concentrations in the CSF. Penetration allowing i3 ester formulations is enhanced by concomitant food intake . 120 Food of most parenteral drugs from the first- and second-generation groups is drug . within the stomach delays gastric emptying and prolongs contact with similarly poor. Parenteral cefuroxime is one exception, and this drug from the the mucosal surface . also has the lowest MICs for common meningeal pathogens among Most Distribution of cephalosporins within the body is governed by the the first- and second-generation cephalosporins .109 The parenteral of 1 to lipid solubility of the drug and the extent of protein binding . third- and fourth-generation drugs, such as ceftriaxone, cefotaxime, compour G3-Lactams bind almost exclusively to albumin . The extent of protein ceftazidime, and cefepime, achieve concentrations that, would allow' largely u 10-115,124 binding can vary from less than 10% to as much as 98% . 108 Because therapy for central nervous system infections .' The presence of ganic ac only unbound drug can pass through capillary pores into interstitial an active transport system that trpnsports many cephalosporins from compom fluid or across cell membranes into intracellular fluid, avidly bound the CSF back to serum contributes to the low drug levels in the CSF portant compounds tend to exhibit high serum concentrations and low tissue with many of the earlier generation drugs . The transport protein in Lion half concentrations . In general, the cephalosporins are largely confined to volved in this system is similar to the protein involved in renal secre- hours, al 121 the extracellular compartment . Drug concentrations in subcutaneous tion of (3-lactam antibiotics. Cefttiaxone, cefotaxime, ceftazidime, with higi blisters, a model for extracellular drug penetration, are similar to those and cefepime exhibit minimal renal tubular secretion and are poor axone ar found in serum . 108 •' 2' Techniques measuring extracellular drug con- substrates for the choroid plexus pump, contributing to higher CSF iary rout centrations in human tissues, such as microdialysis, have demon- concentrations . is a competitive substrate for this pump covered strated that concentrations of unbound drug in interstitial fluid are also and can produce higher concentrationsewith drugs that are effluxed by The u ney neec ment me dosing it of renal Table 20 ceftriaxo GFR (0-S0 GFR 50.91) UsualAdult GFR- less con( Regimen 0 mlimin ' mL/ntin mLmin Him g 1vsu Cephalasp Dosing are prese route are First Generation compote Cefazolin 1 g q8h 0.5-1 g q24h 0.5-1 g ql2h NC Q.5-1 g after 0 .5 g ql2h Cephalothin 1 g q4-6h 0.5 g q8h 0.5 g q6h NC 0.5 g after 1 g ql2h mended Cephapirin 1 g q4-6h 0.5 g q8h 0.5 g q6h NC 0.5 g after l g ql2h hand, fe+ Cephradine 1 g q4-6h 0.5 g q8h 0.5 g q6h NC 0.5 g after I g ql2h than 1W Second Generation mended Cefamandole I g q6h 1 g ql2h l g q8h NC 0.5 g after l g ql2h mofiltrat Cefonicid 1 g q24h 0.125 g q24h 0 .5 g q24h NC None 0 .125 g q24h tients . C Cefuroxime 1 .5 g q8h 0.75 g q24h 0 .75 g q8-12h NC 0.75 g after 0 .75 g g24h Cephamycins removed Cefmetazole 2 g q8-12h 1 g q24h 2 g q24h NC 1 g after 1 g g24h thought i Cefotetan 2 g ql2h 1 g q24h 2 g q24h NC 1 g after I g q24h appropri Cefoxitin 2 g q6h l q ql2h 2 g ql2h 2 g q8h I g after I g ql2h Third Generation ADVER Cefoperazone I g q8h NC NC NC None NC Cefotaxime 2 g q8h 2 g q24h 2 g ql2h NC 1 g after 1 g g24h Ceftazidime 2 g q8h 0.5 g q24h 2 g g24h 2 g ql2h 1 g after 0 .5 g g24h The safe Ceftizoxime 1 g q8h 0.5 g q24h 1 g g24h NC 1 g after 0 .5 g g24h able. Tht Ceftriaxone 1 g q24h NC NC NC None NC is relativ 0 0 .35 g q24h 0.5 g q8h 1 g after 0 .25 g q24h Moxalactam I g q8h .2 g q24h lions (Tt Fourth Generation adverse Cefepime 2 g gl2h 0.5-1 g q24h 13-lacta 1 Oral-First Generation cephalos Cefadroxil 500 mg ql2h 500 mg q24h 500 mg q24h NC 500 mg after 500 mg q- rashes, ( 500 mg after 500 mg Cephalexin 500 mg q6h 250 mg ql2h 500 mg ql2h NC qI , Occur in 500 mg after 500 mg qlZ$ Cephradine 500 mg q6h 250 mg ql2h 250 mg q6h NC hypemn Oral-Second Generation gioedem Cefaclor 500 mg q8h 500 mg ql2h NC NC 500 mg after 500 mg q I reactions Cefprozil 500 mg ql2h 250 mg q24h 500 mg q24h NC 500 mg after 250 mg q2 Cefuroxime (axetil) 500 mg q8h 500 mg q24h 500 mg ql2h NC 500 mg after 500 mg q Howeve, Loracarbef 400 mg ql2h 200 mg q24h 200 mg ql2h NC 400 mg after 400 mg q- serum s Oral-Third Generation cephalos Cefdinir 300 mg g12h 300 mg q24h NC NC 300 mg after 300 mg q 2 dons has Cefditoren 400 mg ql2h 200 mg q24h 200 mg ql2h NC None 200 mg q MaLtiOn; 300 mg after 200 mg q2 Cefixime 400 mg q24h 200 mg q24h 300 mg q24h NC specific Cefpodoxime 200 mg ql2h 200 mg q24h NG NC 200 mg after 200 mg q2 Ceftibuten 400 mg q24h 100 mg q24h 200 mg q24h NC 300 mg after 100 mg q CePhalos CAPD, continuous ambulatory peritoneal dialysis ; GFR, glomerular filtration rate ; NC, no change. 121 sport system. Infection results in higher CSF levels because reactivity. Reports from early studies suggested a much higher fre- anon can enhance penetration as well as interfere with efflux quency of reactions than more recent reports. Most current estimates It suggest a cross-reaction frequency of 5% or less ."' h)ra,ctive transpo . .Few drugs from the cephalosporin class are extensively metabo- Because of the large number of potential haptens thought to be po- , tentially involved, a reliable skin test has not yet been developed . Use lized. The three exceptions are cefotaxime, cephalothin, and ccphapirin, which undergo deacetylation of the acetoxymethyl side of the penicillin skin test to predict cephalosporin reactions is unreli- 111,116 Th metabolic desacetyl products still possess able . For example, in a study of nearly 100 individuals with a history chain in the liver. e ospinal modest microbiologic activity. The elimination half-life of desacetyl- of reaction to the penicillin determinants used in skin testing, only a cefotaxvne is significantly longer than that of the parent compound, single patient who received a cephalosporin had a reaction .140 The 'e oral practical clinical decision to use a cephalosporin in a patient with a 'ration allowing less frequent administration of this otherwise short-half-life 1'3 prior history of reaction to either a penicillin or other cephalosporin cups is drug, The remaining drugs in the cephalosporin class are excreted should be guided by the severity of the prior reaction . Use of is drug from the body unchanged. Most cephalosporins are eliminated by the kidney with half-lives cephalosporins in patients with prior nonsevere, non-IgE-mediated re- among '32.'33 enteral of l to 2 hours. The major mechanism for renal excretion of many actions to other t3-lactams is considered safe . Although the risk of . axime, compounds is tubular secretion . This active transport process is a similar reaction is increased, the reactions are rarely severe I allow largely unaffected by protein binding ."' Probenecid inhibits this or- However, in the setting of a prior IgE-mediated reaction with another . ,nee of ganic acid transport system and can prolong the half-life of these t3-lactam compound, use of a cephalosporin would be discouraged Immunologically mediated reactions to cephalosporins may also s from compounds. For several compounds, glomerular filtration is more im- to CSF portant and protein binding can significantly prolong their elimina- be manifest as hematologic or renal toxicities . is the most ."' For some drugs the elimination half-life is 3 to 8 commonly reported laboratory abnormality."' Cytopenias associated ein in- tion half-life 141 secre- hours, allowing 12- and 24-hour dosing intervals . A few compounds with cephalosporin use are rare . Cytotoxic reactions from im- :idime, with high protein binding and high molecular weights, such as ceftri- munoglobulin antibodies can rarely result in either , e poor axone and cefoperazone, are eliminated to a large extent by the bil- , or anemia ."' Although Coombs laboratory tests ,r CSF iary route-"' From 50% to 70% of active parent compound may be re- have been reported to be positive in a significant percentage of patients covered in the bile and eventually the feces . receiving many of the cephalosporins, these patients most often do not pump 141 xed by The maximal daily doses of agents eliminated primarily by the kid- have hemolytic anemia. This is a false-positive reaction related to ney need to be reduced in renal impairment . Most often this adjust- cross-reactivity that occurs in up to 3% of patients . A similar cytotoxic ment includes both a reduction in dose level and lengthening of the reaction can result in renal damage because of interstitial nephritis ."" dosing interval. Recommended dose adjustments for various degrees The frequency of this reaction appears to be less than with drugs from of renal impairment and for patients receiving dialysis are listed in the penicillin class . Table 20-5 .'29 •' 30 For drugs eliminated by the biliary . system, such as Nonimmunologic hematologic and renal toxicities have been re- ceftriaxone and cefoperazone, dose adjustments are unnecessary un- ported with a similarly low frequency . Bleeding abnormalities have less concomitant severe hepatic insufficiency and renal insufficiency been reported with increased frequency related to two mechanisms . are present.129 The majority of cephalosporins eliminated by the renal Impaired adenosine diphosphate-induced platelet aggregation has route are eliminated by hemodialysis . From 20% to 50% of the parent been reported with moxalactam . 145 This abnormality is not observed 'h compound is removed after a usual dialysis session . It is recom- mended that the drug be given again after hemodialysis . On the other hand, few cephalosporins are removed to any significant extent (less than 10%) by peritoneal dialysis . Additional dosing is not recom- mended after a peritoneal dialysis session . Continuous venous he- Typ Spec~fic Frequency ~24h mofiltration (CVH) is being used more frequently in critically ill pa- 4h tients. Compounds eliminated by the kidneys and hemodialysis are Hypersensitivity Rash 1-3% removed with CVH . Most often the efficiency of drug removal is Urticaria <1% thought to be similar to a creatinine clearance of 10 to 30 mL/min, and <1% appropriate dosing modification is recommended . 131 0.01% Gastrointestinal Diarrhea 1-19% ADVERSE REACTIONS AND TOXICITIES Nausea, vomiting 1-6% Transient transaminase 1-7% h The safety profile of the cephalosporins as a class is generally favor- elevation h able Biliary sludge 20-46%* . The incidence of specific adverse reactions for these compounds Hematologic 4h is relatively similar among drugs within the class with few excep- Eosinophilia 1-10% tions (Table 20-6) . Hypersensitivity reactions are the most common Neutropenia <1 Thrombocytopenia <1-3% '-4h adverse effect associated with cephalosporin therapy, as with other t3-lactam drugs 132,133 Hypoprothrombinemia <1% . The frequency of hypersensitivity reactions to Impaired platelet aggregation <1% 24h cephalosporins is less than that to penicillins . Various cutaneous Hemolytic anemia <1% !2h rashes, often associated with eosinophilia and occasionally fever, Renal 12h occur in 1% to 7% of patients receiving these drugs ."' More severe Interstitial nephritis <1% Central nervous system hypersensitivity reactions such as serum sickness, anaphylaxis, or an- Seizures <1% I2h gioedema occur infrequently . These immunoglobulin E (IgE)-mediated False positive laboratory 24h reactions are estimated to occur in less than 1 in 100,000 patients . 135,136 Coombs positive 3% 24h Glucosuria Rare 24h However, there have been reports of a strong association between .'31,131 The specific Serum creatinine Rare serum sickness in children and use of cefaclor Other 24h cephalosporin product responsible for eliciting the various skin reac- Drug fever Rare 24h tions has not been clearly delineated . Although it is thought that these Disulfiram-like reaction' Rare 24h reactions are hapten mediated, as with related penicillin reactions, the Superinfection Rare Phlebitis Rare 24h specific haptens are not known . Cross-reactivity among drugs from the 24h cephalosporin class and other t3-lactams has been extensively investi- Ceftriaxone . gated, yet controversy remains regarding the reported rates of cross- 'Cephalosporins with thiomethyl tetrazole ring (MTT) side chain . ii the Diagposis-and Management of Infectious Disea

with other cephalosporins . Another coagulopathy is specifically as- CLINICAL USE OF SPECIFIC DRUGS sociated with the MTT side chain present on cefamandole, cefote- tan, cefoperazone, and moxalactam ." The MTT side chain can dis- The usual dosing regimens for adults and children for the various sociate from the parent cephalosporin and act as a competitive cephalosporins by generation are listed in Table 20-7 . The daily doses inhibitor of the vitamin K-dependent carboxylase responsible for to use for serious infections are also listed . converting clotting factors II, VII, IX, and X to active forms . 116 In addition, the side chain (like warfarin) may inhibit vitamin K 2,3- First-Generation Cephalosporins epoxide reductase, which converts vitamin K to its active form."' The first-generation cephalosporins have been extensively used as al. These reactions can lead to prolongation of the prothrombin time ternatives to penicillin for staphylococcal and nonenterococcal strep . and clinically significant bleeding . Patients with poor nutritional tococcal infections. Most commonly, these include skin and soft tissue status, advanced age, and recent surgery on the gastrointestinal tract infections . Among the parenteral first-generation cephalosporins, are at increased risk for clinically significant bleeding .148-151 In ad- cephalothin and cephapirin are no longer available in the United dition, patients with renal failure may be at increased risk for bleed- States . Both drugs were metabolized and rapidly eliminated by renal ing because of the accumulation of the side chain ."' Vitamin K ad- excretion and required frequent dosing . Cefazolin is not metabolized ministration rapidly reverses the abnormality in 24 to 36 hours . The and is eliminated more by glomerular filtration than by tubular excre- MTT side chain can also produce a disulfiram-like reaction with tion .12' Its moderate protein binding slows the glomerular filtration of ethanol ingestion that may persist for several days after antibiotic the drug, resulting in a half-life of 1 .5 to 2 hours, which allows 8- and administration .","' The disulfiram reaction is manifest with flush- 12-hourly dosing . With co-administration of probenecid, cefazolin has ing, tachycardia, headache, sweating, nausea, vomiting, hypoten- been effective in skin and soft tissue infections with once-daily dosingl@ sion, confusion, or blurred vision . The reaction is due to a block in Cefazolin is still recommended in penicillin-allergic patients for more se. alcohol metabolism at the acetaldehyde step resulting in the accu- rious staphylococcal infections, such as endocarditis, even though the mulation of acetaldehyde and subsequent symptoms . drug is more readily hydrolyzed by staphylococcal (3-lactamase than A variety of adverse reactions in the gastrointestinal tract have other first-generation cephalosporins .10.172 Cefazolin is recommended been reported with variable frequency. Diarrhea is the most commonly as the prophylactic antibiotic of choice for foreign-body implantation reported side effect, with rates ranging from 1% to 20% .'34,'54 Upper and many clean and clean contaminated surgical procedures in which gastrointestinal symptoms occur much less frequently . Mild and tran- there is a high risk of infection .111,114 These include cardiac and vascu- sient hepatic toxicity has been reported with most compounds from lar surgery, insertion of orthopedic devices, head and neck surgery that the class, manifest as two- to fourfold elevations in transaminase lev- crosses the oropharyngeal mucosal barrier, vaginal and abdominal els in up to 7% of patients ."' Obstructive biliary toxicity has also been hysterectomy, high-risk cesarean sections, and high-risk gastroduode- .'S6,5 ' reported with ceftriaxone The high biliary ceftriaxone concen- nal and biliary tract procedures . Because of its poor activity against trations have resulted in crystallization of a ceftriaxone-calcium salt Bacteroides species, cefazolin alone is not recommended for infra= and the clinical syndrome of biliary pseudolithiasis . This biliary ab- abdominal procedures that involve the intestine . normality has been reported most commonly in children receiving -The oral first-generation cephalosporins, cephalexin, cephradine, high ceftriaxone doses and in patients with preexisting biliary abnor- and'cefadroxil, have very high oral bioavailability. Cefadroxil has a malities .158 The syndrome is reversible and in most reports has cleared slightly longer half-life than cephalexin and cephradine, which allows in 10 to 60 days after discontinuing the drug . twice-daily dosing instead of the usual four times a day .9' These drugs Adverse reactions in the nervous system are uncommon and are provide appropriate outpatient therapy for many skin and soft tissue similar to those reported with other (3-lactams . Seizures have been re- infections. However, these drugs are not effective for animal bites and- ported in patients with renal insufficiency receiving high doses of scratches involving Pasteurella multocida .175 The drugs are quite ad.-` these drugs . I" Decreased protein binding and inhibition of the choroid tive against Streptococcus pyogenes and provide effective therapy, in plexus pump occur with uremia and may contribute to enhanced tox- streptococcal pharyngitis . 116,17 They have poor activity against peni=' icity in patients with renal impairment . Local phlebitis reactions re- cillin-resistant pneumococci, H. influenzae, and M. catarrhalis, an lated to intravenous administration of the parenteral compounds have are not recommended for sinusitis, otitis media, and lower respiratory, been reported with variable frequency ranging from 1% to 5% .160 On tract infections . The drugs are effective in uncomplicated urinary to,lt the other hand, pain associated with intramuscular administration is infections . However, they are less effective than trimethopriu Howe, 178,179 common with all of the parenteral compounds ."' The local discomfort sulfamethoxazole and fluoroquinolones . cephal can be reduced by use of 1 % lidocaine in diluent . With the exception CSE 18 of once-daily intramuscular ceftriaxone, most parenteral Second-Generation Cephalosporins pirical cephalosporins are administered by the intravenous route . This group includes the cephamycins as well as true cephalospon bents .' The cephalosporins have not been studied extensively in pregnancy . The two groups of drugs have different spectra of antimicrobial ac suscep All drugs in the cephalosporin group are placed in pregnancy class ity and clinical uses . The true cephalosporins have increased actin activir B."' ,"' All of the compounds are secreted to a small degree into breast against H. influenzae, M. catarrhalis, and Neisseria species and co observ 62 milk, but as a class they are considered safe for use in this situation.' parable activity against staphylococci and nonenterococcal stte Mostly In addition to the false-positive Coombs test, laboratory abnormal- cocci. On the other hand, the cephamycins have inferior activity ag with si ities in urine glucose and serum creatinine have been reported with staphylococci but enhanced antibacterial activity against ceft comet, certain cephalosporins . A false-positive glucosuria test performed by Enterobacteriaceae . The cephamycins are especially noted for the reconn the copper reduction technique (Clinitest) has been reported with ce- tivity against anaerobic bacteria, especially B. fragilis. They cefa,n, faclor, cefadroxil, cefamandole, cefonicid, cefotaxime, cefoxitin, and demonstrate good in vitro activity against ESBL-producing strain mfecti ceftazidime.t64 Similarly, a false increase in serum creatinine has been E. coli and K. pneumoniae . However, their reliability in treating in sue inl reported in patients receiving cefoxitin and cephalothin in laboratories tions caused by ESBL-producing strains has not been proved. fectim 65 utilizing the Jaffe technique .' Because of their activity against S. pneumoniae, H. influenzae, activai Because the cephalosporins have broad-spectrum activity, superin- M. catarrhalis, the true second-generation cephalosporins have Cefotti fection or overgrowth of Candida in the gastrointestinal and vaginal bindin 116,111 used extensively for treatment of various respiratory tract infection tracts can occur. Similarly, overgrowth of Clostridium difficile in hospitalized patients .""" Cefuroxime has become the pref have r the gastrointestinal tract with diarrhea and less commonly has agent, compared with cefamandole and cefonicid, because of its I terenni '68 been associated with cephalosporin use. However, the incidence of serum protein binding and improved central nervous system pen Pi ical these superinfections is similar to rates reported with drugs from other tion. Cefuroxime can be used to treat caused by penicl lions antibiotic classes . susceptible pneumococci, H. influenzae, and Neisseria meningitd ie various ally doses

First Generation Cefazolin 0 .5-1 g q8-12h 2 g q6-8h 12 .5-33 mg/kg q6-8h iced as al. Cephalothin 0 .5-1 g q6h 2 g q4-6h 20-25 mg/kg q6h cal strep. Cephapirin 0.5-1 g q6h 2 g q4-6h 10-20 mg/kg q6h soft tissue Cephradine 0 .5-1 g q6h 2 g q4-6h 12 .5-25 mg/kg q6h losponns Second Generation le United Cefamandole 1 g q6h 2 g q4h 12 .5-25 mg/kg q4-6h I by renal Cefonicid 1 g q24h 2 g q24h 50 mg/kg q24h 0 .75-1 .5 g q8h 1 .5 g q8h 12 .5-60 tng/kg q6-8h ,tabolized Cefuroxime Cephamycins ilar excre- Cefmetazole 1-2 g q8h 2 g q6h Not recommended Itration of Cefotetan 1-2 g g12h 2-3 g g12h Not recommended ws 8- and Cefoxitin 1-2 g q6h 2 g q4-6h 20-25 mg/kg q4-6h azolin has Third Generation dosing .'% Cefoperazone 1-2 g g12h 2-4 g q8h Not recommended I g q8-12h 2 g q4-8h 25-30 mg/kg q4-6h r more se- Cefotaxime Ceftazidime 1 g q8-12h 2gg8h 30-50 mg/kg q8h hough the Ceftizoxime 1 g q8-12h 2 g q8-12h 50 mg/kg q6-8h nase than Ceftriaxone 1 g q24h 2 g q12-24h 50-100 mg/kg q24h mmended Moxalactam I g q8h 2gg8h Not recommended plantation Fourth Generation in which Cefepime 1ggl2h 2 g q8-12h 50 mg/kg q8h 1 g g12h 2 g q 12h Not recommended nd vascu- Cefpirome .rgery that Oral-First Generation abdominal Cephalexin 250-500 mg qid 1 g qid 6 .25-25 mg/kg qid Cephradine 250-500 mg qid 500 mg qid 6 .25-25 mg/kg qid trixluode- Cefadroxil 500 mg bid 1 g bid 15 mg/kg bid tv against Oral-Second Generation for intra- Cefaclor 250 mg tid or 375 mg bid 500 gm tid 8 .3-16.7 mg/kg tid Cefprozil 250-500 mg bid 500 mg bid 7 .5-15 mg/kg bid phradine, Cefuroxime (axetil) 250-500 mg bid - 500 mg bid 10-15 mg/kg bid )xit has a Loracarbef 200 mg bid 400 mg bid 7 .5-15 mg/kg bid ich allows Oral-Third Generation lese drugs Cefdinir 300 mg bid or 600 mg qd 300 mg bid or 600 mg qd 7 mg/kg bid or 14 mg/kg qd Cefditoren 200-400 mg bid 400 mg bid Not recommended ;ott tissue Cefixime 200 mg bid or 400 mg qd 400 mg bid 4 mg/kg bid or 8 mg/kg qd bites and Cefpodoxime 200-400 mg bid 400 mg bid 5 mg/kg bid quite ac- Ceftibuten 400 mg qd 400 mg qd 9 mg/kg qd herapy in inst peni- 6a/is, and espiratory nary tract ethoprim- However, it has been largely replaced by third-generation The oral second-generation cephalosporins, including cefuroxime cephalosporins that result in faster eradication of bacteria from the axetil, cefprozil, cefaclor, and loracarbef, are effective for treatment CSF 184 Cefuroxime has been one of the recommended agents for em- of a variety of mild to moderate community-acquired infections . pirical therapy of community-acquired pneumonia in hospitalized pa- Double-tap studies in acute otitis media and acute maxillary sinusitis . 85, losporins tients .' 186 Although cefuroxime has good activity against penicillin- have demonstrated that bacterial eradication is related to the drug's bial activ- susceptible and penicillin-intermediate strains of S. pneumoniae, its ability to produce serum concentrations that exceed the MIC of the :d activity activity against most penicillin-resistant strains is suboptimal . In an infecting pathogen for 40% to 50% of the dosing interval . 10.193 In this and com- observational study of 844 patients with pneumococcal bacteremia, regard, and cefprozil are the best agents for il strepto- mostly related to pneumonia, resistance to cefuroxime was associated S. pneumoniae and are effective against penicillin-susceptible isolates ity against with significantly greater mortality ."' The latest recommendations on and most penicillin-intermediate strains . Cefaclor and loracarbef are ;t certain community-required pneumonia no longer include cefuroxime as a primarily active only against penicillin-susceptible strains . None of r their ac- recommended agent for initial empirical therapy.' 88 Cefuroxime, the oral second-generation cephalosporins provide optimal therapy Fhey also cefamandole, and cefonicid provide effective therapy for other serious for penicillin-resistant pneumococci . For H. inf uenzae and M. ca- strains of infections caused by susceptible pathogens, including skin and soft tis- tarrhalis, cefuroxime axetil would be a more optimal choice than in, infec- sue infections, epiglottitis, complicated sinusitis, and gynecologic in- cefprozil, cefaclor, and loracarbef. Clinical and bacteriologic out- fections .'81,182,189 Cefamandole is more susceptible to (3-lactamase in- comes have demonstrated that 5- to 10-day courses of therapy with I,n,ae, and activation by (3-lactamase-positive strains of H. influenzae . 181 the second-generation cephalosporins are equivalent to or more ef- lave been Cefonicid, which has slow elimination because of its very high protein fective than 10 days of therapy with penicillin V for the treatment of ections in binding of 98%, can be administered once daily . However, failures group A, (3-hemolytic streptococcal pharyngitis. 79a-16 Cefuroxime ax- preferred have occurred in more serious infections, primarily S. aureus bac- etil is also a recommended alternative to doxycycline and penicillin F its lower teremia .182 None of these cephalosporins should be considered for em- for treatment of early Lyme disease. ' 9 ' 1 penetra - Pll1Cal therapy of nosocomial pneumonia or other nosocomial infec- The cephamycins, cefoxitin, cefotetan, and cefmetazole, have pro- )enicillin - tions because of their poor activity against most strains of vided effective therapy for a variety of infections involving aerobic u En ,xitidis .' terobacter, Citrobacter, Serratia, Morganella, and P. aeruginosa. .gram-negative and anaerobic organisms, especially B. fragilis. These lid Maoagenwnt of Infectious Diseases'

infections include intra-abdominal, pelvic, and gynecologic infec- by the emergence of stably derepressed resistant mutants .215- lions of c tions ; infected decubitus ulcers ; diabetic foot infections ; and mixed Combination antimicrobial therapy may be beneficial in reducie e sis .240 The 98_ aerobic-anaerobic soft tissue infections .' 201 Cefoxitin and cefotetan this emergence of resistance resulting from increased chromosoned meningiti are the agents primarily used . Cefotetan has a half-life of 3 to 4 hours f3-lactamase production .216 Organisms containing ESBLs have Third- because of its high protein binding and can be administered twice been observed to fail therapy with cephalosporins even when the, r_ therapy fr daily rather than every 8 hours with cefmetazole and every 6 hours ganism tested susceptible in laboratory tests ." The carbapenems are against N with cefoxitin . Cefmetazole and cefotetan both contain the MTT side the recommended drugs for these ESBL-producing strains . strains . It chain, which increases their potential for hypoprothrombinemia and Cefotaxime, ceftriaxone, and, to a lesser degree, ceftizoxime have and is ust disulfiram reactions . In terms of antimicrobial activity, cefotetan is provided effective therapy for meningitis caused by a variety of dif disease. P .21'-22' more active than cefoxitin and cefmetazole against gram-negative ferent bacteria They are the drugs of choice for meningitis is also hit bacilli but is less active against non-B . fragilis members of the B. fra- caused by H. influenzae and various Enterobacteriaceae .222 Cefo= cervix . In gilis group ."," The significance of these differences is not clear . Of taxime and ceftriaxone also provide effective therapy for meningitis one is re( more importance, as many as 15% of B. fragilis strains can be resis- caused by N. meningitidis and by pneumococci that have MICs of 0 :5 taxime ar tant to the various cephamycins, and drugs with better anaerobic ac- g/mL or less . Organisms with higher MICs have failed monotheripy in patient tivity should be used for empirical therapy of serious Bacteroides in- with these cephalosporins. As a result, empirical therapy with cefo :: lar heart I fections .202 All of the cephamycins are active against N. gonorrhoeae, taxime or ceftriaxone is combined with (with or without both arth, including penicillin-resistant strains. However, recommended therapy rifampin) until the laboratory determines the susceptibility of the with late, for infections with this organism is with ceftriaxone, which is effective pneumococcal isolate ."' If the organism is susceptible to cefotaxime system . A as a single dose .203 Cefoxitin and cefotetan, in combination with doxy- or ceftriaxone, the vancomycin (and rifampin) can be discontinued, is effecti% cycline, provide effective therapy for pelvic inflammatory dis- Treatment of meningitis requires maximal doses of these clines ar ease .204205 For antimicrobial prophylaxis during surgery, cefoxitin and cephalosporins, such as 2,g every 12 hours in adults and 50 mg/kg Ceftriaxo cefotetan are recommended over cefazolin only for colorectal proce- twice daily or 100 mg/kg once daily in children for ceftriaxone and and for se dures and appendectomies."',"' For elective colorectal surgery, cefox- 2 g every 4 to 6 hours in adults and 100 to 150 mg/kg every 4 to 6 Salrnonel itin or cefotetan is still commonly administered even when an oral hours in children for cefotaxime . fective th bowel preparation with erythromycin and neomycin is used . Cefotaxime and ceftriaxone continue to be active against most bac- by gram-) teria producing community-acquired pneumonia. In a large observa= negative I Third-Generation Cephalosporins tional study of pneumococcal bacteremia, resistance to cefotaxime and- fective in The third-generation cephalosporins are major drugs for the treatment ceftriaxone was not associated with higher mortality . 187 Cefotaxime The long of many important infections because of their high antibacterial po- and ceftriaxone were also effective in treating patients with noun enhanced tency, wide spectrum of activity, low potential for toxicity, and favorable meningeal pneumococcal infections, mostly pneumonia, caused b' staphyloc , such as enhanced drug concentrations in the CSF. strains with MICs as high as 2 .g/mLp .223 The National Committee f patient tra They have been especially useful in infections resulting from gram-neg- Clinical Laboratory Standards has created higher susceptibility and red ; sue infect ative bacilli that are resistant to other f3-lactam antibiotics . However, sistaiice breakpoints for pneumococci causing nonmeningeal infect- as monot their superior activity against the Enterobacteriaceae is being challenged tions than for S. pneumoniae causing meningitis.224,225 As a result 6 tococcal, by the increasing frequency of organisms with (3-lactamase-mediated these changes, cefotaxime and ceftriaxone are active against mo resistance . New AmpC f3-lactamases and ESBLs, which inactivate penicillin-resistant pneumococci and are recommended, in combin Fourth-a third-generation cephalosporins, may represent a distinct threat to the tion with a , for empirical therapy for community-acquir The fours continued utility of these agents . pneumonia requiring hospitalization. 185,186,188 Single intramuseu the ceph Cefotaxime, ceftriaxone, ceftizoxime, and ceftazidime are the major doses of ceftriaxone are also highly effective in eradicating H. gram-ne; parenteral third-generation cephalosporins in clinical use for the treat- fluenzae and penicillin-susceptible strains of S. pneumoniae from nut: Serratia ment of nosocomial infections caused by susceptible gram-negative dle ear fluid.226 However, three daily doses of ceftriaxone were re membrai bacilli . Cefotaxime and ceftriaxone are also two of the most potent quired in one study to eradicate penicillin-resistant pneumococci .4 other cep cephalosporins against penicillin-resistant pneumococci . Because of The oral third-generation cephalosporins, which include cefdo by Amp its high protein binding, ceftriaxone has the longest half-life and is cefditoren pivoxyl, cefixime, cefpodoxime proxetil, and ceftibuten, Enteroba usually administered once daily . Ceftizoxime and ceftazidime are approved for oral therapy of mild to moderate respiratory infectio fourth-ge given two or three times daily, and effective dosing of cefotaxime, such as otitis media, sinusitis, and acute exacerbations of chro unlike a which has the shortest half-life, has varied from every 4 hours to twice bronchitis . These drugs have potent activity against H. influenzae cocci. O' daily . Ceftazidime is usually reserved for infections that are likely to their activity against pneumococci is more variable 228-23' Cefdi slightly l involve P. aeruginosa . Cefoperazone is another third-generation cefditoren, and cefpodoxime have activity similar to that of cefut twice dai cephalosporin with modest activity against strains of P. aeruginosa.206 ime and cefprozil and are active against penicillin-susceptibl P. aerug, The availability of the drug in the United States has declined . It differs most penicillin-intermediate strains of S. Cefixime United S, pneumoniae . fepime from the other third-generation cephalosporins in that the majority of tive only against penicillin-susceptible strains, and ceftibuten is . I thicillin the drug is eliminated by biliary secretion . Moxalactam is an oxa- marginal with penicillin-susceptible pneumococci . Short course Cillin-res cephem that has a methoxy group at position 7 similar to that in the most of these drugs have also provided equivalent rates of eradic cephamycins . The drug has activity against gram-negative bacilli sim- 232-235 The t in group A, f3-hemolytic streptococcal pharyngitis . The third-gen ilar to that of other third-generation cephalosporins .207 Both cefopera- creased potency over other oral cephalosporins for E. coli, K. zone and moxalactam have the MTT group at position 3 . Moxalactam tats, the i monia, and Enterobacter, Citrobacter, and Serratia species enh eration c also has an acyl carboxyl group that produces a defect in platelet ag- . their utility for treatment of complicated urinary tract infections lary infer gregation . Significant bleeding complications have been observed with Ceftazidime is the third-generation cephalosporin used for se grattt-net its use, especially when administered three times a day .208 The drug is infections in which P. aeruginosa is documented or highly likely. tissue in not available for use in the United States . one of the recommended drugs, either alone or in combination wt With cot Monotherapy with cefotaxime, ceftriaxone, and ceftizoxime has aminoglycoside, for initial empirical management of febrile when sea provided effective treatment for a variety of nosocomial infections tropenic patients ."' However, ESBLs and AmpC f3-lactamases caused by susceptible gram-negative bacilli, including complicated reduced the utility of ceftazidime for monotherapy. Continuous skin and soft tissue infections, pneumonia, complicated urinary tract lion of ceftazidime has been used to increase trough concentra 209-2'4 traced infections, and intra-abdominal infections, such as However, trials of intermittent versus continuous administration tance to However, cephalosporin monotherapy for infections caused primarily not demonstrated any significant difference in efficacy >a eombi by Enterobacter, Citrobacter, and Serratia species can be complicated Ceftazidime has been effective for the treatment of acute exac .217 .270 chronic pulmonary infections in patients with cystic fibro- febrile neutropenic patients Cefepime appears to require the ad- tan Is . 21 5,216 4 tiogs . The drug 24O CSF and is the treatment of choice for dition of vancomycin less frequently than with ceftazidime reducing The drug penetrates into sisof se- meiungitis caused by PP aeruginosa 241 is one of the recommended agents for the empirical treatment of amosomal Third-generation cephalosporins have also become established vere community-acquired pneumonia when P aeruginosa is sus- have also . 188 The drug's activity against pneumococci is similar to that of ien the or- therapyfor a variety of specific infections . Ceftriaxone is highly active pected . gonorrhoeae, including penicillin- and quinolone-resistant ceftriaxone. Cefepime has demonstrated results comparable to those enems are against N . It is the drug of choice for all forms of gonococcal infection with ceftriaxone in patients with community-acquired pneumonia re- strains 1,172 and is used in combination with doxycycline for pelvic inflammatory quiring hospitalization ." The drug penetrates well into CSF and xtme have disease, proctitis, and proctocolitis . 204a42 A single oral dose of cefixime produces outcomes similar to those with cefotaxime in acute bacterial ety of dif. of the meningitis .273 .274 Although emergence of resistance during therapy meningitis is also highly effective for uncomplicated gonococcal infections cervix, urethra, and rectum .243 .244 Single-dose intramuscular ceftriax- may be less of a problem with the fourth-generation cephalosporins, it Cefo. . 204 Ceftriaxone and cefo- does occur. Many of the new ESBLs, especially the new CTX-M en- meningitis one is recommended therapy for chancroid taxin1e are recommended therapy for treatment of early Lyme disease zymes, can inactivate these fourth-generation drugs. ;ICs of 0 .5 motherapy in patients with neurologic involvement or third-degree atrioventricu- ." 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