Fourth-generation cephalosporins

Clinical Microbiology Newsletter Vol. 19, No. 17

Fourth-Generation

September 1, 1997

Cephalosporins

Joan C. Fung-Tome, Ph.D. Department of Microbiology Bristol-Myers Squibb Company Wallingford, CT 06492

Since the discovery of cephalosporin in 1945, modifications of its chemical structure have led to a large number of semisynthetic derivatives with increased potency and antibacterial spectrum. These derivatives have been categorized into generations based largely on their antibacterial spectrum. The first generation cephalosporins (represented by cefazolin, cephaloridine, cephalexin, cephalothin) have good activities against gram-positive bacteria (GPB) and, because of their lability to P-lactamases, to a limited number of gram-negative bacteria (GNB). Secondgeneration cephalosporins (represented by cefuroxime and cefamandole) are more stable to P-lactamases and thus have enhanced activities against GNB, but their activities against GPB are compromised. Cephamycins (cefoxitin and cefotetan) are often grouped with the second-generation cephalosporins because of their similar activities to aerobic bacteria. The third-generation cephalosporins (represented by cefotaxime, ceftazidime, ceftriaxone, and cefoperazone) are characterized by their good activity against GNB. Third-generation cephalosporins (3G ceph.) with activity against Pseudomonas aeruginosa generally have weak activity against GPB, while those retaining activity to GPB are inactive against P. aeruginosa. Since the improvement in antibacterial activities between the first and third generation cephalosporins are incremental, categorization of a cephaCMNEEJ 19(17)129-136.1997

losporin has sometimes differed among investigators. The fourth-generation cephalosporins (represented by cefepime, cefpirome, cefoselis, cefclidin, cefozopran, and cefquinome) have broad antibacterial spectra that encompass GNB, including P. aeruginosa and GPB. Their enhanced activities against GNB can be attributed to their poor affinity for and increased stability to the Bush group 1 P-lactamases, and to their more rapid penetration across the outer membrane of bacterial cells. Collectively, the thirdand fourth-generation cephalosporins have been referred to as extended-spectrum cephalosporins. Limited microbiological and clinical data on cefoselis, cefclidine, cefquinome, and cefozopran are published in the English literature, and data on these compounds are included in this review when available. Cefepime and cefpirome are used clinically in several countries for the treatment of moderate to severe bacterial infections. However, cefepime is currently the only fourth-generation cephalosporin (4G ceph.) approved for clinical use in the United States.

to the entrance of the porin channel (1).

In Vitro Spectrum and Potency The in vitro spectrum and potency of the 3G and 4G ceph. can be distinguished in two ways: by the overall spectrum of the compounds to unselected clinical bacterial isolates (Table l), and to strains with known mechanisms of resistance (Table 2). Against members of the family Enterobacferiaceae, all of the cephalosporins listed were active against E. coli, Klebsiella spp., and Proteus mirabilis. However, the 4G ceph. had greater activity for Proteus vulgaris, Morganella morganii, Citrobacterfieundii, Enterobatter spp., and Serratia marcescens, spe-

cies that can be induced or mutationally derepressedto produce very high levels of their chromosomal p-lactamases. In tests with Pseudomonas aeruginosa, cefepime and ceftazidime were equally active, whereas cefpirome and cefquinome were slightly less active. Cefoselis, cefclidine, and cefozopran were the most active cephalosporins against P. aeruginosa. These extendedspectrum cephalosporins had variable activities to other Pseudomonas, Burk-

Chemical Structure The chemical structures of the 4G ceph. are shown in Figure 1. These agents contain at position 7p a methoxyimyl-aminothiazole (or -aminothiadiazolyl, in the case of cefclidine) moiety as present on cefotaxime and ceftriaxone. However, unlike most 3G ceph., with the exception of ceftazidime, the 4G agents contain a positively charged quaternary nitrogen at position 3. The positive charge is believed to orient the cephalosporin Elsevia

In This Issue Fourth-Generation Cephalosporins . . , . . . . . . , , . . . . 129 Newer extended-spectrum cephalosporins with improved activity against Enterobacter spp., Citrobacter fieundii, Serratia marcescens, indole positive Proteus and other species with Bash group 1 @lactamases offer increased treatment options

0196-4399/9760.00

+ 17.00

CH,--R

HP

R

X Cefepime

C

(BMY 28142)

-4 3 Cefpirome

Cefoselis

C

(HR-810)

C

(FK-037)

NH 2

I

CH,-CH,-OH Cefozopran

Cefquinome

Cefclidine

C

(SCE-2787)

C

(OCI 2556. HR 11 lv)

N

(E 1040)

ONH,

Figure 1. Chemical structures offourth-generation cephalosporins.

holderia, and Acinetobacter species. They were inactive against Stenotrophomonas maltophilia based on their MIC,,, though the MIC,,, for the extended-spectrum cephalosporins can be 43 l.tg/ml. The 4G ceph. were active against methicillin-susceptible staphylococci, and should be considered as being inactive against methicillin-resistant strains, even though cefoselis had lower MIC values to the latter strains. Cefclidine was about lo-fold less active than other 4G ceph. for GPB. Cefepime, cefpirome, and cefoselis were comparable to

cefotaxime in their activities for streptococci, including strains of viridans streptococci and Streptococcus pneumoniae that were less susceptible or resistant to penicillin. The extended-spectrum cephalosporins were active against strains of Moraxella catarrhalis and Haemophilus influenzae, irrespective of their plactamase production. None of these cephalosporins had activity against activity against Bacteroides fragilis. Since their introduction, the 3G ceph. have been used extensively. They are poor inducers of the Bush group 1p-

lactamases of Citrobacter spp., Enterobatter spp., indole-positive Proteus, and P. aeruginosa and have remained active against fi-lactamase-inducible strains. However, stably derepressed mutants can be selected from j3-lactamase-inducible populations of these enteric species to give rise to isolation rates exceeding 20% in some institutions with E. cloacae (6). These P-lactamases-hyperproducing strains are resistant to 3G ceph. and the extent of their susceptibility to 4G ceph. varies with the drug (Table 2). Whereas 2325% of ceftazidime-resistant E. cloacae strains were resistant to cefpirome and cefoselis, only 67% were resistant to cefepime. More importantly, cefepime was effective in the treatment of infections caused by ceftazidime-resistant strains of Enterobacter spp. (34). The 4G ceph. are less active to high p-lactamase producers of P. aeruginosa. However, cefepime was active against 8 1% of cefotaxime-resistant P. aeruginosa strains and >19% of ceftazidimeresistant strains (Table 2). In a recent survey, cefepime was active against 97% of the enteric and 50% of the nonenteric (Pseudomonas, Acinetobacter, and Flavobacterium spp.) strains that were resistant to ceftazidime (35). The extended-spectrum cephalosporins are active against the most common, plasmid-mediated P-lactamases (TEM1, TEM-2, and SHV- 1) encountered in Escherichia coli and Klebsiella spp. (Table 3). Since the mid-1980s there has been a rapid increase in the number of mutant enzymes that leads to variable levels of resistance to 3G ceph. Production of the extended-spectrum plactamases (ESBLs), particularly with newer SHV derivatives, can lead to decreased susceptibility to the 4G ceph. Though the MICs to 4G ceph. are often c16pg/ml, higher MICs can be obtained using higher inocula of the ESBL-containing strains. As a cautionary note, the NCCLS recommends that laboratory reports should indicate that ESBL-producing strains may be resis-

NOTE: No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability. negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. No suggested test or procedure should be carried out unless. in the reader’s judgment, its risk is justified. Because of rapid advances in medical sciences, we recommend that the independent verification of diagnoses and drug dosages should be made, Discussions, views, and recommendations as to medical procedures, choice of drugs, and drug dosages are the responsibility of the authors. Clinical Microbiology Newdefter (ISSN 0196-4399) is issued twice monthly in one indexed volume per year by Elsevier Science Inc.. 655 Avenue of the Americas, New York. NY 10010. Subscription price per year: $222.00; for orders outside of the United States, Mexico and Canada: $302.00. Second-class postage paid at New York, NY and at additional mailing offices. postmaster Send address changes to Clinical Microbiology Newslencr, Elsevier Science Inc., 655 Avenue of the Americas. New York. NY 10010. For customer service phone (212) 633-3950; TOLL-FREE for costotnexs in the U.S.A and Canada: l-888-4ES-INFO (1-888437436) or fax: (212) 633-3680.

130

0196-4399/97/$0.00

+ 17.00

~3 1997 Elsevier Science Inc.

Clinical Microbiology

Newsletter 19:17,1997

tant clinically to all cephalosporins (39).

Factors Determining Spectrum and Potency In GNB, three factors influence the antibacterial activity of a p-lactam. First is the ability of the P-lactam to penetrate the outer membrane of GNB. Second, since resistance to j3-lactams is commonly the result of P-lactamase production, interactions of the p-lactams with these enzymes are important parameters. The third factor is the affinity of the target enzymes for the j3-lactam. The ability of a P-lactam to penetrate through the porin channels of the gramnegative outer membrane is determined by its size and charge (40). Zwitterionic compounds (i.e., those with a positive and a negative charge at physiological pH) such as the 4G ceph. permeate more rapidly through the porin channels than compounds with a net negative charge, as found with most 3G ceph. (Table 4). Cefepime, cefpirome, and cefclidine permeate the porin channels of E. coli and E. cloacae at least five times more rapidly than does ceftazidime. The cephalosporins penetrate IOO- to XJO-fold more slowly across the outer membrane of P. aeruginosu compared with that of E. coli. The poorer penetration of compounds across the outer membrane of pseudomonads accounts for its intrinsic resistance to many antibacterial agents. The extended-spectrum cephalosporins are relatively stable to the Bush group 1 p-lactamases (Table 5). Though the 4G ceph. have slightly higher Vmaxvalues than the 3G ceph., the newer agents are highly resistant to hydrolysis by the group 1 p-lactamases. This is because these enzymes have poor affinities (high K,) for the 4G ceph. (Table 5). The group 1 P-lactamase had 1,OOO-lO,OOO-fold lower affinities for cefepime, cefpirome, and cefclidine than for cefotaxime, and lOlOO-fold lower than ceftazidime. The affinity of a P-lactamase for a cephalosporin is an important parameter at low p-lactam concentrations encountered in the periplasmic space; a cephalosporin that binds well to a P-lactamase may be more efficiently hydrolyzed than one that binds poorly to the enzyme. The targets of p-lactam antibiotics are enzymes, known as penicillin-binding proteins (PBPs), located on the Clinical Microbiology Newsletter 19:1?.1997

outer layer of the inner membrane. In the Enterobacteriaceae and P. aeruginom, the high molecular weight PBPs

(PBP lA/lB, PBP 2, and PBP3) are enzymes involved in the latter stages of peptidoglycan biosynthesis. Binding of p-lactams to these enzymes leads to their inactivation and cell death, Like most cephalosporins, the extended-spectrum cephalosporins bind preferentially to PBP 3 (Table 6). However, unlike the other cephalosporins, the E. coli PBP 2 and E. cloacae PBP 2 also have high affinities for cefepime. Cefoselis binds to the PBP 2a of methicillin-resistant S. uureus (IC,,, 3 pg/ml); however, the clinical use of cefoselis for the treatment of MRSA infections remains unproven (44).

Resistance Development The emergence of resistance to 3G ceph. in GNB has occurred primarily through the selection of mutants with derepressed production of chromosomal p-lactamases or the acquisition of plasmids encoding ESBLs. To determine the likelihood of resistance development to 4G ceph. with clinical use, studies examining the isolation rates of resistant mutants following a single or repeated exposure to these agents have been carried out. These in vitro studies can only address the potential for chromosomal mutations that can lead to resistance. the influence of resistance via plasrnid-mediated P-lactamasesis dependent on the prevalence of ESBL-containing strains within the geographical area. The 4G ceph. are much more active (>lO-fold) than the 3G ceph. against GNB species containing the Bush group 1 p-lactamases. Because of their enhanced activities, spontaneous mutants with decreased susceptibility to 4G ceph. can be selected following exposure to lower concentrations of these agents, than when tested with higher concentrations of 4G ceph. (44,46). The single-step mutants selected with the extended-spectrum cephalosporins remain, for the most part, susceptible to 4G ceph., though they are often resistant to 3G ceph. (46,47). Only following repeated exposure to 4G ceph. are mutants with high-level resistance to these drugs isolated. These findings suggest that multiple mutations, which are less likely to occur, are needed to achieve high-level resistance to 4G ceph. These mutations have led to hy8 1997Elsevier ScienceInc.

per-production of the Bush group 1 plactamases and to porin deficiencies, two key factors that affect the antibacterial activity of 4G ceph. against GNB (46,47,48).

Conclusion The 4G ceph. are dipolar ionic compounds, which accounts for their enhanced permeation across the outer membrane of GNB. The decreased affinities of the Bush group 1 P-lactamases for these cephalosporins and their relative stability to these enzymes explain the activities of 4G ceph. against 3G ceph. resistant strains of Enterobacter spp., Citrobacter spp., and indole-positive Proteus. In vitro studies indicate that resistance to the 4G ceph. is slower to develop than that of the 3G ceph. Resistance to 4G ceph. is often a combination of hyper-production of chromosomal p-lactamases, acquisition of plasmid-mediated ESBLs, and porin deficiency. Because of their extended spectrum and increased potency, the 4G ceph. cefepime and cefpirome, are being used in the treatment of moderate to severe bacterial infections. References

1. Hancock, R.E.W. and F. Bellido. 1992. Factorsinvolved in the enhancedefficacy againstGram-negativebacteriaof fourth generationcephalosporins.J. Antirnicrob. Chemother.29 (Suppl.A): l-6. 2. Duval, J., et al. 1993.In-vitro antibacterial activity of cefepime: A multicenter study. J. Antimicrob. Chemother.32 (Suppl B):55-61. 3. Liu, P.Y.-F., et al. 1995.Comparisonof susceptibility to extended-spectrumplactam antibiotics and ciprofloxacin amonggram-negativebacilli isolated from intensive care units. Diagn. Microbiol. Infect. Dir,. 22:285-291. 4. Fekete,T., et al. Comparativesusceptibilities of Kiebsieila species,Enterobatter species,and Pseudomonas aeruginosa to 11 antimicrobial agents in a tertiary-care university hospital. Am. J. Med. 100 (Suppl. 6A):20S-25s. 5. Alcaide, F., et al. 1995.In vitro activities of 22 P-lactamantibiotics against penicillin-resistant and penicillin-susceptible viridans group streptococciisolated from blood. Antimicrob. Agents Chemother.39:2243-2247. 6. Thomsbeny,C., et al. 1993.In-vitro activity of cefepimeand otherantimicrobials: surveyof Europeanisolates.J. Antimicrab. Chemother.32 (Suppl B):31-33. 7. Chong, Y.. K. Lee., and O.H. Kwon. 1993.In-vitro activities of cefepime 0196-4399/97/$0.00+ 17.00

131

2.2 2.1 0.7 3 20 50 32 NT 32 >lOO >I6 1.5 >I6 1.6 >I6 10.03 0.08

1.2 2.3 0.4 0.7 14 NT 22 NT 21 10 >I6 2.8 >I6 2 >16 0.07 0.1

Citrobacter freundii

Serratia marcescens

Pseudomonas aeruginosa

Pseudomorux jluorescens

cepacia

baumanii

anitratus

1~08

Burkholderia

Acinetobacter

Acinetobacter

Acinetobacter

Staphylococcus aureus MS

Staphylococcus aureus MR

Staphylococcus epidennidis

Enterococcus faecalis

Streptococcus pyogenes

Streptococcus pneumoniaea 0.2 0.8 3

Pen-Sensitive

Pen-Intermediate Pen-Resistant

mdtophilia

aerogenes

Enterobacter

Stenotrophomonas

cloacae

Enterobacter

--

0.2

0.1

SO.3

nwrganii

Morganella

0.5 1.5

O..l

0.5

1.4

50.3

Proteus vulgaris

MS

0.1

so. 1

10.3

Proteus mirabilis

NT NT NT

1

0.6

0.13

264

18

%4

12

35

NT

NT

NT

25

3.2

2.1

3.5

0.2

1.4

0.7

0.06 0.5

<0.03

>32

0.5

30

1.3

>32

1

23

8

21

NT

2.8

3.9

2.2

11

5.4

0.2

0.5

0.3

0.4

SO.1

so.3

Klebsiella

0.1

so. 1

50.3

Klebsiella pneumoniae

0.1 0.2

<0.06

so.1

so.3

Escherichia coli

Cefclidine

0.2

Cefoselis

Cefpirome

oxytoca

cephalosporins

Fourth-generation

values (pghnl) of extended-spectrum Cefepime

Table 1. Geometric mean MICw

NT

NT

NT

0.4

10.01

50

1.6

43

1.8

>16

NT

NT

NT

25

NT

24

5.8

0.2

7

7

0.3

0.9

10.1

0.03

50.05

0.2

Cefquinome

I.

NT

NT

NT

0.1

0.03

35

3.3

20

1

64

NT

32

NT

16

NT

4.4

1.3

0.06

5

0.3

0.5

6.2

0.2

0.07

0.2

0.08

Cefozopran

>8

0.9 .8

0.6

0.2

>16

20

xi4

20

>16

x54

34

32

7

18

16

5.2

>16

116

~16

4.5

10.5

SO.5

0.3

0.8

go.5

Cefiazidime

-..

1

0.7

0.03

SO.06

10.03

>32

7.1

>32

2.9

>64

>64

>32

>64

13

NT

32

12

14

>32

>32

0.8

1

10.5

50.5

0.8

SO.5

^_

Cefotaxime

Third-generation

.-.

2

0.5

0.06

co.2

10.03

>64

4

>64

2.3

xi4

21

244

32

>64

NT

>64

6.1

>64

>64

z-54

2.5

>12

so.5

0.4

0.5

10.5

Ceftriaxone

mean MICw

0.08 0.06 0.12 >loo 5,9-l 1,14, 16, 17.20-30

0.1 0.1 0.1 >32 2-19

injluenzaeb

p-lactamase negative

P-lactamase positive 5, 12, 14-17, 27-31

>32

0.4

0.06

0.07

0.07 1 5.1 1.4

Cefoselis

10,22,26,30

>32

0.25

0.12

0.5

NT NT NT 1.9

Cefclidine

0.3

0.8

9-11,24.25

>5O

NT

NT

26,32

>64

NT

NT

0.3

NT

NT 0.04

NT NT

Cefozopran

NT NT

Cefquinome

(continued)

s32 [67%]

8.0 [2%] 1.6 3.1 >I00 NC [67%]

<32 [26%] 3.1 12.5 .I00 NC [90%]

NC [53%]

>I00 [94%]

3.1-16 [14%]

12.5-216[23%]

>loo

>I00

25

NC [<81%]

NC [19%]

NC [O%]

16[6-7%]

Ceftazidime

resistantto: Cefotaxime

P. aen&nosa

3-6,8, 13, 14, 20-21

10.03 34

10.03

0.3

0.25 2 8 0.5

Ceftriaxone

C. fieundii

b Resistant being ME 532 @ml (except ceftriaxone. 564 @ml). ’ 81% represents % resistant plus moderately susceptible, i.e., MICS 116 ccg/m.

NC, not calculated. a References: 7.23.26.34-37.

Ceftriaxone

Ceftazidime

Cefozopran

Cefclidine

Cefoselis

Cefpirome

Cefepime

SO.04 100

SO.03

0.01

0.25 1.6 8 0.6

Cefotaxime

3,4,6-12, 14, 3,543, 11, ld 16-24,26-32 16, 18,19,22-

>64

0.25

0.12

0.2

0.25 16 16 0.2

Ceftazidime

Third-generation

E. cloacae

MICm (erg/ml)[% resistantlb

Table 2. Activities of fourth-generation cephalosporins to cefotaxime- and/or ceftazidime- resistant clinical isolate9

NT, not tested; MS, methicillin-sensitive; MR, metkicillin-resistant; Pen, penicillin. a Unspecified penicillin susceptibility. b Unspecified b-lactamase production.

References

Bacteroides fragilis

catawhalis

Pen-Sensitive Pen-Intermediate Pen-Resistant

Haemophilus

Moraxella

Cefpirome

cephalosporius

Fourth-generation

of extended-spectrum

0.12 0.8 5.1 1.5

Cefepime

values (@ml)

0.25 2 8 1.1

Streptococcus viridausgroup

Table 1. Geometric

Table 3. Activities of extended-spectrum p-lactamasesa

cephalosporins against E. coli strain C600-containing

plasmid-mediated

MC (MW) Cefepime

Cefpirome

Cefoselis

Cefclidine

Cefquinome

Ceftazidime

C600b TEM-1 TEM-2 TEM-3 TEM-4 TEM-5 TEM-6 TEM-7 TEM-8 TEM-9 SHV-1 SHV-2 SHV-3 SHV-4 SHV-5

SO.06 50.06 0.5 4 8 2 4 8 8 8 0.5 16 4-16 2->16 2-16

10.12 SO.12 0.5 8 8 2 4 8 8 8 0.5 16 116 516 16

10.06 $0.06 0.25 16 32 4 4 4 8 8 1 32 8 4 16

0.12 ND ND 8 8 4 8 16 16 16 ND 32 16 32 8

50.12 10.12 0.5 8 16 1 4 4 4 ND 0.5 16 16 >16 8

10.25 0.25 0.5 216 >16 >16 >16 >16 >16 >16 2 >16 >16 >16 216

10.12 so.25 SO.25 >32 >32 4 2 0.5 4 2 10.25 >32 32 >32 32

OXA- 1 OXAOXA-

1 SO.06 50.06

1 so.12 50.12

0.12 SO.06 10.06

ND ND ND

1 10.12 10.12

0.25 0.25 0.12

SO.25 10.25 $0.25

p-lactamases

Cefotaxime

ND, not determined. aReferences11. 15.22. bAll @lactamase-producing strains are transconjugates of E. coli strain C600. C600 doesnot contain a b-lactamaseresistanceplasmid.

Table 4. Rates of permeation of extended-spectrum porin channelsa

cephalosporins through

Permeability coefficient of cells (nm/sec) E. coli OmpF 750 643 464 95 175

Cefepime Cefpirome Cefclidine Ceftazidime Cefotaxime

E. cloacae F porin

P. aeruginosa outer membrane

15 14 11 1 5

5 1 2

aReference:40. against Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa and other aerobic Gram-negative bacilli. J. Antimicrob. Chemother. 32 (Suppl. b):21-29. 8. Liu, Y.-C., W.-K. Huang, and D.-L. Cheng. 1994. Antibacterial activity of cefepime. Chemotherapy 40:384-390. 9. Ishida, Y., et al. 1995. In vitro and in vivo activity of DQ-2556, a new cephalosporin. Chemotherapy 41:5-13. 10. Tanaka, M., M. Otsuki, and T. Nishino. 1992. In vitro and in vivo activities of DQ-2556 and its mode of action. Antimicrob. Agents Chemother. 36:25952601. 11. Murphy, S.P., M.E. Erwin, and R.M. Jones, 1994. Cefquinome (HR 1llV). 134

0196-4399/97/$0.00+ 17.00

In vitro evaluation of a broad-spectrum cephalosporin indicated for infections in animals. Diagn. Microbial. Infect. Dis. 20:49-55. 12. Neu, H.C., N.-X. Chin, and H.-B. Huang. 1993. In vitro activity and B-lactamase stability of FK-037, a parenteral cephalosporin. Antimicrob. Agents Chemother. 37:566-573. 13. Washington, J.A., et al. 1993. Multicenter comparison of in vitro activities of FK-037, cefepime, ceftriaxone, ceftazidime, and cefuroxime. Antimicrab. Agents Chemother. 37:169&1700. 14 Sprangler, S.K., et al. 1994. Susceptibilities of 177 penicillin-susceptible and -resistant pneumococci to FK 037, cefpirome, cefepime, ceftriaxone, cefo8 1997Elsevier ScienceInc.

taxime, ceftazidime, imipenem, biapenem, meropenem, and vancomycin. Antimicrob. Agents Chemother 38:898900. 15. Jones, R.N., M.S. Barrett, and M.E. Erwin. 1994. In-vitro activity of FK-037, a new parenteral cephalosporin. J. Antimicrob. Chemother. 33:137-144. 16. Martinez-Belt&i, J. et al. 1995. Multicenter comparative study on the antibacterial activity of FK-037, a new parenteral cephalosporin. Eur. J. Clin. Microbial. Infect. Dis. 20:27-32. 17. Clarke, A.M., S.J.V. Zemcov, and M.M. Hubinette. 1994. Comparative in vitro activity of FK-037, a new cephalosporin antibiotic. Diagn. Microbial. Infect Dis. 20:27-32. 18. Kessler, R.E., et al. 1985. Comparison of a new cephalosporin, BMY 28142, with other broad-spectrum B-lactam antibiotics. Antimicrob. Agents Chemother. 27:207-216. 19. Thomsberry, C., and Y. Cheung. 1996. Comparative activity of eight antimicrobial agents against clinical bacterial isolates from the United States, measured by two methods. Am J. Med. 100 (Suppl. 6A):26A-38s. 20. Yokota, T., K. Arai, and E. Suzuki. 1991. Cefpirome, its in vitro antibacterial activity, binding affinity to the site of action, PBPs, and synergy of bacClinical Microbiology Newsletter 19:17,1997

Table 5. P-lactamase parameters of extended-spectrum Parameter cephalosporin

cephalosporin9

E. cloacaeb

C. ji-eundiib

P. aeruginosab

TEM-1

100 0.04-0.09 0.016-0.36 0.11 0.2 0.04 0.001-0.01 0.005409

100 (o.oo6)c (0.416) (0.011) 0.005 0.0002-0.005 (0.002)

100 0.05 0.18-0.75 1.0 0.05 0.15 0.002-0.08 0.002-0.02

100 2.4 3.7-6.3 2.0 0.8

159 40

87-204 35-148

5,000 4,000

385 3 0.9-l .2

400-941

3,000

3-16 0.03

>3o,ooo 9,500

Hydrolysis of cephalosporin, relative V,, Cephaloridine Cefepime Cefpirome Cefoselis Cefclidine Cefquinome Ceftazidime Cefotaxime Affinity for cephalosporin, K, (uM) Cefepime Cefpirome Cefoselis Cefclidine Cefquinome Ceftazidime Cefotaxime Ceftriaxone

58-180 130-330 25 300-313 29 3-17 0.05-0.2 0.1

0.72 2.4

aReferences1,24, 30,40-43. bBush group 1 &lactamase ‘Values in parenthesesare relative VW, with cepahlothin set at 100.

Table 6. Affinities

of extended-spectrum

cephalosporins for PBPsa GI bkdmUb

PBP

Cefepime

Cefpirome

Cefoselis

Cefclidine

Cefquinome

Ceftazidime

E. coli

1A 1B 2 3 4

1.5 0.25 0.03 16

6.5 0.4-2.6 2.5-9.7 0.01-0.1 5-16

2.7 1.3 7.3 0.03 3.9

14->25 2 7.8~>25 ~0.2-0.5 1.2-10

0.7-1.6 0.6-1.7 4.9-9.6 0.02-0.09 2.8-16.6

0.6-l .2 l-2.7 >25-80 0.05-0.2 >lOO

E. cloacae

1A 1B 2 3 4

1.0 1.8 0.2 0.03 10

0.3 1 7.8 0.03 >lOO

NT

NT

0.06 5.8 >lOO 0.1 0.3

0.9 6.2 >lOO 0.06 >I00

P. aeruginosa

1A 1B 2 3 4

0.04 0.75 >25 co.003 0.04

<0.04-0.07 5.2-6.6 >25 <0.04-0.03 0.07-0.2

0.08 2.7 >25 0.04 0.1

0.5-0.8 1.3-17 >25 <0.003-<0.2 0.6-l .9

NT

Species

0.1

7.3-10 >25 0.08-o. 1 1.8-2.2

NT, not tested. aRefercnces: 10,24, 30, 31,33,42,44. bIC50, concentration of cephalosporin required to inhibit [3H] benzyl penicillin binding by 50%.

teridical effect with serum complement or mouse cultured macrophages. Chemotherapy 39 (Suppl. 1): 1l-20. 21 Bergeron, M.G., and M. Bernier. 1994. Bactericidal activity of cefpirome (HR 810) agains Gram-negative bacteria isolated form blood of septicemic patients. Infections 22:299305. Clinical Microbiology Newsletter 19:17,1997

22. Jones, R.N., et al. 1991. Antimicrobial activity of E-1040, a novel thidiazolyl cephalosporin compared with other parenteral cephems. Diagn. Microbial. Infect. Dis. 14:301-309. 23. Watanabe, N.-A., R. Hiruma, and K. Katsu. 1992. In vitro evaluation of E1077, a new cephalosporin with a broad antibacterial spectrum. Antimi0 1997Elsevier ScienceInc.

crab. Agents Chemother. 36:589-597. 24. Fujimoto, T. et al. 1990. In-vitro antibacterial activity of DQ-2556 and its stability to various P-lactamases. J. Antimicrob. Chemother. 26:329-341. 25. Limbert, M. et al. 1991. Antibacterial activities in vitro and in vivo and pharmacokinetics of cefquinome (HR 11lV), a new broad spectrum cepha0196-4399/97/.$0.00+17.00

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losporin. Antimicrob. Agents Chemother. 35:14-19. Iwahi, T. et al. 1992. In vitro and in vivo activities of SCE-2787, a new parenteral cephalosporin with a broad antibacterial spectrum. Antimicrob. Agents Chemother. 36:1358-1366. Wise, R., J.M. Andrews, and D. Thomber. 1994. The in vitro activity of FK037, a new broad spectrum injectable cephalosporin. J. Antimicrob. Chemother. 34:629-637. Inoue, K., E. Inoue, and S. Mitsuhashi. 1995. In vitro antibacterial activities of FK037: A new parenteral cephalosporin. Chemotherapy 41:257-266. Ohki, H. et al. 1993. FK037, a new parenteral cephalosporin with a broad antibacterial spectrum: Synthesis and antibacterial activity. J. Antibiot. 46:359-361. Mine, Y. et al. 1993. In vitro antibacterial activity of FK037, a novel parenteral broad-spectrum cephalosporin. J. Antibiot. 46:359-361. Watanabe, N.-A. et al. 1988. In vitro evaluation of E1040, a new cephalosporin with potent antipseudomonal activity. Antimicrob. Agents Chemother. 32:693-701. Klein, 0. et al. 1994. In vitro activity of SCE-2787, a new cephalosporin with potent activity against Pseudomonas aeruginosa and members of the family Enterobacteriaceae. Antimicrob. agents Chemother. 38:289&2901. Pucci, M.J. et al. 1991. Comparison of cefepime, cefpirome, and cefaclidine binding affinities for penicillinbinding proteins in Escherichia coli K- 12 and Pseudomonas aeruginosa SC8329. Antimicrob. Agents Chemother. 35:2312-2317.

Editors Mary Jane Ferraro Paul A. Granato

Josephine A. Morello R.J. Zabransky 0 1997 Elsevier Science Inc. ISSN 0196-4399 CMNEEJ 19(17)129-136, 1997 Elsevier

34. Sanders, W.E., Jr., J.H. Tenney, and R.E. Kessler. 1996. Efficacy of cefepime in the treatment of infections due to multiply resistant Enterobacter species. CIin. Infect. Dis. 23:454-461. 35. Jones, R.N., and S.A. Marshall. 1994. antimicrobial activity of cefepime tested against Bush group 1 P-Iactamase-producing strains resistant to ceftazidime. Diagn. Microbial. Infect Dis. 19:33-38. 36. Fung-Tome, J. et al. 1989. Activity of cefepime against ceftazidime- and cefotaxime-resistant Gram-negative bacteria and its relationship to p-lactamase levels. Antimicrob. Agents Chemother. 33:498-502. 37. Sanchez, M.L., and R.N. Jones. 1993. Antimicrobial activity of FK-037 against class I P-lactamase producing species resistant to ceftazidime: A multi-laboratory clinical isolate sample. J. Antimicrob. Chemother. 32:654-656. 38. Sader, H.S., and R.N. Jones. 1994. In vitro antimicrobial activity of cefpirome against ceftazidime-resistant isolates from two multicenter studies. Eur. J. CIin. Microbial. Infect Dis. 13:675-679. 39. National Committee for Clinical Laboratory Standards. 1997. Methods for dilution antimicrobial susceptibility tests for bacteria that grows aerobically. M7A4. NCCLS. Wayne, PA. 40. Nikaido, H., W. Liu, and E.Y. Rosenberg. 1990. Outer membrane permeability and P-lactamase stability of dipolar ionic cephalosporins containing methoxyimino substituents. Antimicrab. Agents Chemother. 34:337-342. 41. Phelps, D.J. et al. 1986. Affinity of cephalosporins for P-lactamases as a factor in antibacterial efficacy. Antimicrab. Agents Chemother. 29:845-848.

42. Then, R.L. and P. Angehm. 1985. Ways to overcome cephalosporin-mediated P-lactam resistance in Enterobacter cloacae. Chemioterapia 4:83-89. 43. Watanabe, N.-A., and K. Katsu. 1992. Cefclidin (E1040), a novel cephaIosporin: Lack of selection of P-lactamase overproducing mutants in an in vitro pharmacokinetic model system. J. Antibiotics 45: 1335-1345. 44. Mine, Y. et al. 1993. Excellent activity of FK037, a novel parenteral broadspectrum cephalosporin, against methicillin-resistant staphylococci. J. Antibiot. 46:99-l 19. 45. Watanabe, N.-A., and K. Katsu. 1992. Bactericidal activity of cefclidin (E1040) against Pseudomonas aeruginosa under conditions simulating plasma pharmacokinetics: Lack of development of chromosomally-mediated resistance to p-lactams. J. Antimicrob. Chemother. 30:475-487. 46. Fung-Tome, J.C. et al. 1996. Differences in the resistant variants of Enterobatter cloacae selected by extended-spectrum cephalosporins. Antimicrob. Agents Chemother. 40: 12891293. 47. Fung-Tome, J. et al. 1988. Frequency of in vitro resistance of Pseudomonas aeruginosa cefepime, ceftazidime, and cefotaxime. Antimicrob. Agents Chemother. 32:1443,1961445. 48. Chen, H.Y., and D. M. Livermore. 1993. Activity of cefepime and other plactam antibiotics against permeability mutants of Escherichia coli and Kt’ebsiella pneumoniae. J. Antirnicrob. Chemother. 32 (SuppI B):63-74.

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Clinical Microbiology Newslener is abstracted in Tropical Diseases Bulletin, Abstracts on Hygiene and Communicable Diseases and Current AIDS Literature. 8 1997Elsevier ScienceInc.

Clinical Microbiology Newsletter 19:17.1997