ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, April 1978, P. 657-664 0066-4804/78/0013-0657$02.00/0 Copyright ©) 1978 American Society for Microbiology

Vol. 13, No. 4

Printed in U.S.A.

Cefuroxime, a Beta-Lactamase-Resistant Cephalosporin with a Broad Spectrum of Gram-Positive and -Negative Activity HAROLD C. NEU* AND KWUNG P. FU Departments of Medicine and Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York 10032 Received for publication 1 August 1977

The in vitro activity of cefuroxime, a cephalosporin antibiotic, was investigated against 604 isolates and compared with the activity of other fl-lactam compounds. Cefuroxime had activity comparable to that of other cephalosporins, including cefamandole and cefoxitin, against streptococcal and staphylococcal species; most streptococci were inhibited by 0.1 ,ug or less per ml, and staphylococci were inhibited by 1.6 ,ug or less per ml. Enterococci were relatively resistant. Cefuroxime inhibited ,B-lactamase-producing Neisseria gonorrhoeae and Haemophilus influenzae. Cefuroxime had excellent activity against members of the Enterobacteriaceae; 83% of,-lactamase-producing Escherichea coli, 100% of Salmonella, 100% of Klebsiella, 90% of Proteus mirabilis, 95% of Citrobacter, 56% of Enterobacter, and 58% of Shigella were inhibited by 12.5 ,ug/ml. Cefuroxime had activity comparable to that of cefamandole and cefoxitin; it inhibited isolates of E. coli and Klebsiella resistant to cefamandole and inhibited Enterobacter and Citrobacter resistant to cefoxitin. Many isolates of Serratia, some indole-positive strains of Proteus, and Bacteroides fragilis were resistant to cefuroxime. Resistance of cefuroxiime to hydrolysis by ,-lactamases played a major role in its activity against both gram-positive and gram-negative organisms. There has been a proliferation of new cephalosporin and cephamycin compounds in the past few years. Although compounds such as cephalothin and cephapirin have proven to be useful in the treatment of serious infections produced by gram-positive and gram-negative bacilli, the agents are not active against many ,8-lactamaseproducing members of the Enterobacteriaceae. There has been a steady increase in the level of cephalosporin resistance in some species such as Escherichia coli and Klebsiella pneumoniae; but more important has been the apppearance in hospitalized patients of organisms "intrinsically resistant" to cephalosporins such as cephalothin and cefazolin. Although newer aminoglycosides have been developed, these compounds carry a significant degree of toxicity particularly if used for prolonged periods. Penicillin allergy is a problem in many individuals with serious infection, and clinical studies have indicated that allergic cross-reactions between penicillins and cephalosporins occur rarely (i.e., in less than 10%. of patients). For these reasons we have evaluated the in vitro activity of cefuroxime, a new cephalosporin with increased resistance to f8-lactamase hydrolysis. We have compared its activity with that of other cephalosporiiiM and of currently available penicillins in order to determine

whether this compound, a molecularly modified agent, would be useful.

MATERIALS AND METHODS Cefuroxime was a generous gift of Glaxo Pharmaceuticals. All other antimicrobial agents were given by their respective manufacturers. Fresh dilutions of the compounds were prepared daily in sterile medium or distilled water. Bacterial isolates included recent blood and sputum isolates from patients hospitalized at the Columbia-Presbyterian Medical Center and isolates saved over the past 10 years because of the presence of kfiown /1-lactamases. Isolates do not represent outbreaks as far as can be determined by antibiograms or typing. Susceptibility tests. Antimicrobial activity was measured by agar dilution or broth methods previously described, using Mueller-Hinton (MH) broth or agar (3, 4). An inoculum of 10i colony-forming units (CFU) was used unless specified. Minimal inhibitory concentration (MIC) was defined as the lowest concentration of antibiotic that inhibited development of visible growth on agar or in broth. Minimum bactericidal concentration (MBC) was determined by plating 0.1 ml from clear broth tubes to blood agar. The effect of growth medium was determined by using brain heart infusion (BHI), Trypticase soy (TS), nutrient, and Columbia media, all purchased from BBL. ,B-Lactamase assays were performed by using purified enzymes or crude extracts as specified (2, 5). The 657

658

NEU AND FU

ANTIMICROB. AGENTS CHEMOTHER.

microiodometric or spectrophotometric assay was used (2, 6). RESULTS

RESULTS

Table 1 shows the overall in vitro activity of cefuroxime against 604 bacterial isolates. Cefuroxime had excellent activity against gram-positive cocci and bacilli; all of the streptococci tested (S. viridans, S. pyogenes, S. agalactiae, and S. bovis) except for S. faecalis and S. faecium (true enterococci) were inhibited by 0.4 ,ug or less per ml, and more than 50% were inhibited by 0.1 jig/ml. Non-,8-lactamase-producing staph-

ylococci, whether S. aureus or S. epidermidis,

were inhibited by 0.2 jig or less per ml, but the MICs for fB-lactamase-containing isolates were 0.8 to 6.2 ,ug/ml. Methicillin-resistant S. aureus and S. epidermidis were inhibited by 1.6 to 6.2 ,ug/ml. Strains of cephalothin-resistant S. epidermidis were inhibited by 1.6 ,ug or less of

cefuroxime per ml. The fastidious gram-negative cocci and bacilli, Neisseria gonorrhoeae, N. meningiditis, and Haemophilus influenzae, were inhibited by 0.2 to 1.6 ,ug/ml. This included /3-lactamase-producing N. gonorrhoeae and H. influenzae.

TABLE 1. In vitro activity of cefuroxime Species

No. of isolates

Streptococcus viridans ..... S. pneumoniae . . S. pyogenes ..... S. agalactiae ... S. fecalis ....... S. bovis ....... Staphylococcus

10 10 21 20 30 10

100

28 13

64 54

10

30

10 10 4

70 30

aureus ....... S. epidermidis Haemophilus influenzae ..... Neisseria meningitidis ....... N. gonorrhoeae Listeria ........ Pasturella multocida ....... Clostridium .... Fusobacterium Escherichia coli Salmonella ..... Shigella ........ Citrobacter .....

5

6 5 60 31 19 22

400

100

100

3

10

3.1

100 100 20

26 27

40 45 42 64

63 84

77

95

90 28 3

96 46

100 56 16

85 15 27

37 72

100

100

Klebsiellapneumoniae ...... Enterobacter ... Serratia ....... Proteus mirabilis P. morganii .... P. rettgeri ...... P. vulgaris ..... Providencia .... Acinetobacter Pseudomonas aeruginosa ... Pseudomonas, other ........ Bacteroides fragilis ......... B. melaninogenicus ..........

31 32 30 20 32

10

18

5

6 28 16

3

58 10 30

3

11

16 21 12

22

25 31

39 37

57 43

59 20 90 75 77 68 56

68 26

71 30

84 40

84 83

87 89 16

96 94

69

89 81

86 62

93 46 100 100

100 100 100

33 92 87

100 100 100

20

100

20

100

17 10

6 100

18

24

59

76

100

VOL. 13, 1978

659

CEFUROXIME

At a concentration of 12.5 jig/ml, which is readily attained after 0.5 to 1.0 g given intramuscularly (1), 83% of E. coli strains, 100% of Salmonella, 58% of Shigella, 95% of Citrobacter, 100% of K. pneumoniae, 56% of Enterobacter, 90% of P. mirabilis, 72% of Proteus rettgeri, and 57% of Providencia were inhibited. However, only 16% of Serratia marcescens, 37% of Proteus morganii, and 43% ofAcinetobacter strains were inhibited by 12.5 ,ug/ml. None of the various types of Pseudomonas species was inhibited, and less than 20% of Bacteroides fragilis strains were inhibited by 25 ,g/ml. At concentrations of 100 ,ug/ml, 59% of B. fragilis strains were inhibited. Table 2 shows the effect of growth medium on the MIC and MBC. There were no major differences in the MICs and MBCs determined in MH, BHI, TS, soy, National Institutes of Health (NIH) (Difco), Columbia, and nutrient broths. All assays were run at the usual pH values of the medium, which ranged from 6.9 to 7.4. The effect of pH of the medium was also determined by using MH broth adjusted to pH 6, 7, and 8. E. coli, K. pneumoniae, Serratia, and P. morganii were used as test organisms. Regardless of the pH of the medium, the MICs were identical. MBCs were also identical to MICs or only twofold greater. To determine the effect of agar and broth on the MIC, representative susceptible (MIC less than 12.5 ,ug/ml) and resistant Enterobacteriaceae were inoculated onto nutrient agar, MH agar, and BHI agar containing cefuroxime. The MICs either were identical or differed by only twofold in either direction for each medium. It is clear that the osmolality and conductivity of the medium did not alter either the MICs or the

MBCs of cefuroxime for either susceptible or resistant organisms, since there were marked differences in osmolality and conductivity of the media used. The osmolality of the TS broth, MH agar, and BHI agar was 440 mOsm, and the conductivity was 12 mS. The osmolality of the NIH medium was 200 mOsm and conductivity 6 mS, whereas the osmolality of nutrient broth was 60 mOsm and conductivity was 1.5 mS. The effect of inoculum size upon MICs is given in Table 3. With those organisms for which the MIC was very low, there was a two- or fourfold increase in the cefuroxime MIC as the inoculum increased from 103 to 107 CFU. For some organisms that contained f8-lactamases, such as certain indole-positive Proteus and Enterobacter species, the MICs were low with 103 CFU but exceeded 200 Ig/ml (i.e., the strains were resistant) when the inoculum contained 107 CFU. It should be noted, however, that even with 107 CFU the MIC of cefuroximne was 12.5 ,ug or less per ml against isolates for which the ampicillin MICs were in excess of 400 Lg/ml and cephalothin MICs were greater than 400 ,ug/ml. Table 4 gives a comparison of MICs and MBCs for Enterobacteriaceae. The MBC was identical or only twofold greater than the MIC in the majority of instances tested except for Enterobacter species in which the organisms fell into two distinct groups. For the smaller group, the MBC was 64-fold greater than the MIC. The activity of cefuroxine compared with other cephalosporins is shown in Table 5. Cefuroxime had activity equivalent to that of cephalothin and penicillin G against Streptococcus pyogenes. Its activity against Staphylococcus aureus was equivalent to that of cefamandole, but cefuroxime was less active than cephalothin

TABLE 2. Effect of growth medium on MICs and MBCs of cefuroxime MIC (MBC) (pg/ml) on given mediuma

Species

NB

Escherichia coli ..........

Col

TSB

BHI

NIH

MH

25

25 (25) 50

6.2 (12.5) 50

12.5 (25) 25

12.5 (12.5) (25)

6.2 (12.5) 25

(50)

(50)

(50)

(50)

(50)

(50)

6.2

(6.2) E. coli ...................

Klebsiella pneumoniae

....

6.2

(6.2) Proteus morganii .........

Serratia marcescens

......

Enterobacter cloacae

......

(6.2)

1.6

1.6

12.5

(1.6)

(1.6)

(12.5)

6.2 (6.2)

50

50

25

50

25

25

(50)

(50)

(50)

(50)

(50)

(50)

100

(200) S. marcescens ............

6.2

100 (200)

100

100

200

200

(200)

(400)

(400)

(400)

50

50

50

50

200

12.5

(50)

(50) 50 (50)

(100) 50 (100)

(50)

(200)

(12.5)

50

(100) a NB, Nutrient broth; Col, Columbia.

50

100

50

(100)

(200)

(50)

660

ANTIMICiOoB. AGENTS CHEMOTHER.

NEU AND FU

TABLE 3. Inoculum effect on MICs of cefuroxime

Resistance to 83-lactamase hydrolysis by cefuroxime correlated well with the inhibitory activity of the compound. It was clearly not enSpecies 107 CFU 105 CFU 103 CFU tirely stable to /3-lactamase activity as was cefoxitin, since the f-lactamases of selected species 50 25 12.5 Escherichia coli ...... such as some Enterobacter cloacae and Proteus 3.1 3.1 0.8 E. coli ............... 12.5 3.1 1.6 Shigella sonnei ....... morganii could hydrolyze the compound. In 12.5 12.5 6.2 Serratia ............. many ways the resistance of cefuroxime to /8>200 200 25 Serratia ............. lactamase hydrolysis was similar to the resist3.1 6.2 3.1 Klebsiella of cefamandole, but cefuroxime was more ance 6.2 12.5 12.5 Klebsiella ............ to hydrolysis. Some strains such as E. resistant >200 200 25 Proteus morganii ..... coli 3337 or the Citrobacter were resistant even 100 12.5 >200 P. vulgaris ........... though the isolates did not destroy cefuroxime. 6.2 1.6 0.8 P. mirabilis .......... In this regard, cefuroxime resembled the activity 200 200 200 Enterobacter cloacae of cefoxitin against Enterobacter and Citrobac25 12.5 3.1 E. aerogenes ......... 25 6.2 100 Citrobacter ........... ter (4). 25 1 0.4 Staphylococcus aureus Although intact bacterial cells did not hydro12.5 1 0.2 S. epidermidis ........ lyze cefuroxime, it was possible that strategically placed /8-lactamases could hydrolyze the compound as it entered the bacterial cell. For this partially purified 8-lactamase preparaagainst staphylococci. Cefuroxime was less ac- reason, tions were used to determine the resistance of tive than cefazolin and cefamandole against cefuroxime to destruction compared with other Streptococcus faecalis. Against non-fl-lacta- agents. Cefuroxime resistant to hydrolysis mase-producing E. coli, cefuroxime had activity by the most commonwas E. coli TEM-type enzyme, similar to that of cefamandole and cefoxitin, and had the a 100-fold greater ability to hyagainst cephalothin-resistant E. coli cefuroxime which drolyze cephaloridine than cephalothin (Table was also equal in activity to these agents. CefuSimilarly, an oxacillin-hydrolyzing Shigella roxime was more active than other cephalospo- 8). sonnei /8-lactamase did not hydrolyze cefuroxrins against ,8-lactamase-containing Salmonella Of importance is the fact that cefuroxime and inhibited all at 12.5,ug/ml. Its activity was imne. /3-lactamases that did also greatest of the agents tested against Shi- was not hydrolyzed by such those in some hydrolyze cefamandole, gella. Cefuroxime was the most active cephalo- Klebsiella, Acinetobacter, andasProvidencia. sporin tested against Klebsiella and Citrobacter. acted as a competitive inhibitor Against Enterobacter the activities of cefurox- of Cefuroxime the G and ampicillin hydrolysis ime and cefamandole were comparable; 60% of by E. coli TEM. ofIt penicillin a less useful is, however, isolates were inhibited by 12.5 ,ug/ml. Cefurox- inhibitor than semisynthetic penicillins such as ime was less active than cefamandole and cefox- oxacillin. itin against indole-positive Proteus. Cefuroxime and cefamandole had similar activity against DISCUSSION Serratia, Providencia, and Acinetobacter, and This study demonstrates that cefuroxime has both were less active than cefoxitin against Ser- an impressive antibacterial spectrum. From the ratia and Providencia, but more active against MIC (ug/ml) at:

Acinetobacter. Table 6 gives a direct comparison of cephalothin, cefuroxime, cefamandole, and cefoxitin against 8-lactamase-producing organisms. It is apparent that the three new agents had similar activity against many organisms. However, there may be an eightfold difference in MICs of the three agents against a particular species. Resistance to hydrolysis by /3-lactamases. Organisms that were resistant to cephalosporins were selected for study to determine the degree of hydrolysis of cefuroxime by intact bacteria. Table 7 shows the susceptibility (MICs) of the organisms to cephalothin, cephaloridine, cefuroxime, cefamandole, and cefoxitin and the amount of antibiotic hydrolyzed.

TABLE 4. Comparison of MICs and MBCs of cefuroxime MBC greater by folda No tested Identical 2 >16

Species

Escherichia coli

10 3 7 10 8 2 Enterobacter cloacae 10 2 4 Salmonella ........... 5 2 3 5 2 4 Shigella sonnei ....... Citrobacter freudii .... 5 1 4 Proteus morganii ..... 10 5 5 P. vulgaris ........... 5 2 3 Serratia marcescens .. 5 5 a None showed 4-, 8-, or 16-fold differences. ......

Klebsiella pneumoniae

4

CEFUROXIME

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VOL. 13, 1978

CEFUROXIME

data presented, it appears that its actiyity is demonstrable against both the common grampositive cocci and gram-negative bacilli involved in serious hospital infections, and also those microorganisms that are resistant to the older cephalosporins. In the present study, cefuroxime's activity was little influenced by the medium used for assay, and it was bactericidal over a wide pH range. Furthermore, the compound's activity was not affected by the osmolality or conductivity of the TABLE 6. Activity of newerparenteral cephalosporins against cephalothin-resistant isolates MIC (pg/mi) Species

Cephalo- Cefaman- e thin dole Cefoxt

Escherichia coli 400 Klebsiellapneu400 moniae Enterobacter 400 cloacae Serratia marcescens .>400 Citrobacter 400 freundii . 400 Shigella sonnei Salmonella ty-

phimurium

100

Acinetobacter 400 Proteus morganii >400 P. rettgeri . >400 P. vulgaris . >400 Providencia 400 stuarti . Bacteroides fra-

gilis .200

Cefurox-

1.6

3.1

ime 12.5

1.6

3.1

3.2

1.6

200

3.1

12.5

6.2

12.5

3.2

100 12.5

1.6 25

200

1.6

3.1 12.5 25 200

3.1 12.5 12.5 3.2

6.2 3.1 50 50 >400

1.6

25

50

25 3.1

25

200

663

medium as occurred with some of the f3-lactam compounds. The size of the inoculum used in assays did not increase the MICs or MBCs of the compound. Except for some Enterobacter isolates, MICs and MBCs were identical or differed by only twofold. At levels that have been achieved in humans (1), cefuroxime inhibited the majority of Enterobacteriaceae that are the commnon causes of pneumonitis, septicemia, and deep-tissue infections. It also inhibited most cephalothin-resistant isolates at levels readily achieved in serum or urine. The activity of this new compound against gram-positive coccal species was equivalent to that of cephalothin and cefazolin, the agents most widely used at present. Cefuroxime was as active as the new agent cefamandole and was more active than cefoxitin, the new ,8-lactamaseresistant cefamycin, against staphylococci and streptococci. Cefuroxime had greater activity than cephalothin against E. coli, K. pneumoniae, P. mirabilis, and Citrobacter. Its activity was similar to that of cefamandole and cefoxitin against many /8-lactamase-producing Enterobacteriaceae. The activities of cefuroxime and cefamandole paralleled each other with minor differences; i.e., cefuroxime was superior because of its greater resistance to fl-lactamase hydrolysis.

Unfortunately, cefuroxime was not active against a number of Serratia and P. rettgeri isolates that are resistant to both cephalosporins and to aminoglycosides (7). These organisms possess type I ,8-lactamases. An important feature of the activity of cefuroxime is that against the 83-lactamase-producing N. gonorrhoeae and H. influenzae, which contain type III fl-lactamases.

TABLE 7. Susceptibility of organisms in comparison with the amount of antibiotic hydrolyzed Species

Escherichia coli 3337 E. coli 1189 Klebsiella Enterobacter Enterobacter Citrobacter Serratia Acinetobacter Providencia Proteus mor-

Cephalothin Cephaloridine MIC % Hydro% Hydro(,g/ml) lyzeda (pg/ml) lyzed >400 100 100 100

Cefuroxime Cefamandole MIC % Hydro- MIC % Hydro(pg/ml) lyzed (ug/ml) lyzed

Cefoxitin MIC % Hydro(pg/ml) lyzed

100

0

12.5

0

400

0

100 100 100 100

6.3 3.1 1.6 200 400 12.5 1.6 1.6 200

6.3 200 0.8 200 100 12.5 0.8 3.1 100

0 50 0 50 0 0 100 0 75

3.1 1.6 100 400

100 100 100 50 50

0 0 0 25 0 0 0 25 22

0 0 0 0 0

MIC

12.5 100 200 400 400 400 200 400 400

50 50 100 100 100 50 100 100 100

50 400 100 400 400 400 100 200 400

400 6.3 1.6 1.6 12.5

0 0

0

ganii P. mirabilis

3 26 0.8 16 3.1 25 Organisms at a concentration of 109/ml were incubated with the antibiotics for 60 min at 35°C. The amount of antibiotic remaining was calculated by agar diffusion assay using Bacillus subtilis or Sarcina lutea. a

400

100

400

50

664

NEU AND FU

ANTIMICIROB. AGENTS CHEMOTHER.

TABLE 8. Comparison of hydrolysis of cephalosporins Hydrolysis (umol/min per mg of protein) Source of 8-lactamase

Type of ,8-lactamasea Cephalothin

II Escherichia coli .......... ....... II Klebsiella ... ..................... IV Proteus mirabilis ......... ....... I Citrobacter freundii .............. I Enterobacter .................... Providencia ...............I...... IV Acinetobacter .................... III E. coli ...

274 158 255 268 64 35

Cefuroxime 0

0 0 0 0 0 0 0 0 0

Cefamandole

Cefoxitin

0 168 88 0 0 25

0 0 0 0 0 0

225 205 0 5 0 0 II 10 0 0 Shigella sonnei ........... ....... 33 Proteus morganii ......... ....... V 0 0 a Richmond classification. ,B-Lactamases were prepared from the organisms listed. Hydrolysis of the compounds was detennined by use of the spectrophotometric assay, and the number of micromoles hydrolyzed was calculated from standards.

Evaluation of fl-lactamase hydrolysis of cefuroxime indicates that resistance to destruction is the major factor in its extended spectrum of activity. However, some organisms are resistant without hydrolyzing the compound. It is not possible to predict this. Furthermore, knowledge of the susceptibility of an organism to cefamandole or to cefoxitin will not allow one to predict the susceptibility of the organism to cefuroxime.

6.

LITERATURE CITED

7.

1. Foord, R. D. 1976. Cefuroxime: human pharmacokinetics. Antimicrob. Agents Chemother. 9:741-747. 2. Neu, H. C. 1971. f?-Lactamase production by Pseudomonas aeruginosa, p. 534-536, Antimicrob. Agents Chemother. 1970. 3. Neu, H. C. 1974. Cefamandole, a cephalosporin antibiotic

8.

4.

5.

with an unusually wide spectrum of activity. Antimicrob. Agents Chemother. 6:177-182. Neu, H. C. 1974. Cefoxitin, a semisynthetic cephamycin antibiotic: antibacterial spectrum and resistance to hydrolysis by gram-negative beta-lactamases. Antimicrob. Agents Chemother. 6:170-176. Neu, H. C., and E. B. Winshell. 1972. The relation of ,8-lactamase activity and cellular location to resistance of Enterobacter to penicillins and cephalosporins. Antimicrob. Agents Chemother. 1:107-111. Novick, R. P. 1962. Microiodometric assay for penicillinase. J. Biochem. 83:236-240. O'Callaghan, C. H., R. B. Sykes, A. Griffiths, and J. E. Thornton. 1976. Cefuroxime, a new cephalosporin antibiotic; activity in vitro. Antimicrob. Agents Chemother. 9:511-519. Richmond, M. H., and R. B. Sykes. 1973. The fi-lactamases of gram-negative bacteria and their possible physiological role. Adv. Microb. Physiol. 9:31-88.

Cefuroxime, a beta-lactamase-resistant cephalosporin with a broad spectrum of gram-positive and -negative activity.

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, April 1978, P. 657-664 0066-4804/78/0013-0657$02.00/0 Copyright ©) 1978 American Society for Microbiology Vol...
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