Comparative activity of eight antimicrobial agents against clinical bacterial isolates from the united states, measured by two methods

Comparative Activity of Eight Antimicrobial Agents Against Clinical Bacterial Isolates from the United States, Measured by Two Methods Clyde Thornsberry,

PhD, Y. Cheung Yee, frank/in, Tennessee

In a surveillance study conducted during 19921993 at 83 medical institutions of different types and sizes (e.g., laboratories, community hospitals, teaching hospitals) and from different geographical areas of the United States, clinical bacterial isolates were tested for their susceptibility to eight comparative antimicrobial agents (cefepime, ceftazidime, cefotaxime, ceftriaxone, ciprofloxacin, gentamicin, imipenem, and piperacillin). A total of 12,574 isolates were tested by either the Etest method (AB Biodisk) or a microdilution method (MicroScan) in the participating laboratories; 11.8% of these isolates were subsequently retested for quality assurance purposes by both methods in a central laboratory. The results obtained in the central laboratory were essentially the same as the results obtained in the participating laboratories. This article presents data for gram-negative and grampositive isolates other than Streptococcus pneumoniae, the results of which have been previously published. Antimicrobial susceptibility results obtained with the two different minimum inhibitory concentration (MIC) methodsMicroScan and Etest-showed that most isolates of Enterobacteriaceae were susceptible to cefepime, exceeding the activity of ceftazidime, ceftriaxone, and cefotaxime, principally because of the greater activity of cefepime against the species that produce Bush group 1 p-lactamases (predominantly Enterobacter cloacae, Enterobacter aerogenes, and Citrobacter freundii). In addition, the activity of cefepime against Pseudomonas aeruginosa isolates was essentially equivalent to that of ceftazidime and greater than that of third-generation cephalosporins. Most methicillin-susceptible Staphylococcus aureus were susceptible to all the cephalosporins, whereas methicillin-resistant S. aureus and enterococci were resistant.

From MRL Pharmaceutical Services, Franklin, Tennessee. Requests for reprtnts should be addressed to Clyde Thornsberry,

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Overall, the most active antimicrobials in this study were imipenem, ciprofloxacin, and cefepime, but the activity of all the antimicrobials varied with different species. Categorically, the results from the microdilution and Etest methods were equivalent. Am J Med. 1996;1OO(suppl6A):26S-38S. efepime is classified as a fourth-generation cephalosporin because of its unique molecular structure that gives it a well-balanced spectrum of activity against gram-negative and gram-positive pathogens, including bacteria that produce Bush group 1 ,&lactamases.l~” Thus, cefepime is resistant to hydrolysis by most P-lactamases, including most of the extended-spectrum cephalosporinases (i.e., extended TEMs) .‘l-13 Because it contains both a positive and a negative charge, with a resulting net neutral charge, cefepime is reported to penetrate the bacterial cell membrane of gram-negative bacteria at a significantly faster rate than the third-generation cephalosporins.“-” The bacteria most likely to produce the Bush group 1 fi-lactamases are species of PseudflmIono,s, Entwobacter, Citrobacter, Proteus, Morganella, and Serratia’4-16; isolates that produce this enzyme are resistant to most P-la&am antibiotics, including the third-generation cephalosporins.lT Almost all of these isolates, however, are susceptible to cefepime.“~‘sCefepime is also active against many enteric species (e.g., Klebsiella pnewnoniae, Escherichia COG)that produce extended-spectrum cephalosporinases“jl’ and, in general, its activity is equivalent to or exceeds that of the third-generation cephalosporins against most clinically relevant gram-negative and gram-positive pathogens.‘“-” We have previously found the activity of cefepime against Pseudomonas aeruginosa. to be similar to that of ceftazidime but greater than that of cefotaxime and ceftriaxone. lQMany of the species that produce Bush group 1 P-lactamases are among the most frequent causes of severe infections.2”,24Recent studies in our laboratory suggest that the incidence of constitutively produced Bush group 1 ,&lactamases in Enterobacter cloacae probably exceeds 20% (unpublished data) ; these isolates are resistant to third-generation cephalosporins. Therefore, an antimicrobial agent

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such as cefepime, with an extended spectrum that includes activity against species that produce Bush group 1 p-lactamases and are resistant to third-generation cephalosporins, as well as those susceptible to third-generation cephalosporins, is clinically important. In this surveillance study conducted in 1992- 1993, we determined the activity of cefepime versus that of other antimicrobial agents used for the treatment of serious infection against bacterial pathogens isolated in geographically and demographically diverse hospitals and laboratories in the United States. Both the MicroScan microdilution and the Etest methods were employed. Data presented include gram-positive and gram-negative clinical isolates other than S. pneumoniae, the results of which have been previously published.‘”

MATERIALS

AND METHODS

To determine the minimum inhibitory concentration (MIC) values for the bacterial isolates in this study, we compared results obtained using the Etest (Al3 Biodisk; Solna, Sweden) with those of a conventional microdilution method’” (the trays were produced for this study by MicroScan; Dade International, Sacramento, CA). The Etest is performed in much the same way as a disk diffusion test.27 A plastic strip containing a concentration gradient of the antimicrobial agent is used. The organism to be tested is inoculated ont.0 an agar plate in the same manner as for the standard disk diffusion method,” and the Etest strip is placed on the inoculated surface. Differential amounts of antibiotic then diffuse from the strip into the agar. The MIC of the antimicrobial can be read directly from the strip at the point where it meets the elliptical zone of inhibition. The Etest may be useful for obtaining the MIC values of agents, such as cefepime, that are not yet on t,he available commercial susceptibility testing panels. A total of 83 institutions in 27 states were enrolled in the study. These institutions ranged in size from 100to > 1,000 beds, but the majority contained either 400-600 or >l,OOO beds. Most of the institutions were university-affiliated teaching institutions or community hospitals (with or without teaching programs), but a few Veterans Administration and military hospitals, and some private, state, and reference laboratories were also included. Clinical isolates to be tested included a wide range of gramnegative and gram-positive species, including enterococci and methicillin-resistant strains of staphylococci (MRSA). S. pneumoniae isolates were tested but reported in a separate publication.‘” The reference strains recommended by the National CommitJune

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tee for Clinical Laboratory Standards (NCCLS) were tested for quality control. Each laboratory was assigned to perform susceptibility testing by either the NCCLS microdilution methodZfi or the Etest method,“’ and the Imaterials for performing the assigned system were supplied to each laboratory. Antimicrobial susceptibility tests were performed on consecutively isolated bacterial pat.hogens (without duplicating isolates). The isolates were then shipped t,o a central control laboratory (Franklin, TN), where they were subcultured, their identification confirmed, and then stored at approximately - 70” C. Approximately loo/oof the isolates from each participating institution were randomly selected for testing by both the microdilution and t,he Etest methods at the central laboratory. Therefore, each participating laboratory determined either a broth microdilution MTC or an Etest MIC on their isolates, and the central laboratory determined both tests on a subset of all isolates. The data from the central laboratory served as a qualiqy control mechanism for regional testing. The microdilution trays were prepared specifically for this study by MicroScan and included appropriate concentrations of cefepime, ceftazidime, ceftriaxone, cefotaxime, piperacillin, imipenem, ciprofloxacin, and gentamicin (the antimicrobial powders were obtained from t.he respective manufacturers and were designated for antimicrobial susceptibility testing). The concentrations of the antimicrobials tested varied from ~0.015 to 512 pg/mL, depending on the drug. (See tables for specific concentration for each drug.) The Etest strips for cefepilme, ceftazidime, ceftriaxone, ciprofloxacin, and -imipenem were supplied by AB Biodisk. Etest strips for gentamicin, cefot,axime, and piperacillin were not available at the time the study was conducted, and therefore only MicroScan results are available for these antimicrobials. The microdilution MIC values were det,ermined according to the recommendations of the NCCLS,“” and the Etests were performed according to the recommendations of the manufacturer. The susceptibility data from each institution were forwarded to the central laboratory for analysis.

RESULTS

--

In this shady, 8,165 gram-negative and 4,409 grampositive isolates were tested in the participating laboratories. In laborat,ories using the Etest method, 9,353 isolates were tested, and in laboratories using the MicroScan method, 3,221 isolates were testied. The organisms tested in t.he pa.rticipaGng laboratories, along with their results, were forwarded to the central laboratory where 11.8%of the organisms were randomly selected and tested by both the MicroScan and the The American

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Etest methods. The data from the participating laboratories were combined and analyzed. The major purpose of the testing in the central laboratory was to have a database to which data from the participating laboratories could be compared. A comparison of the data from the participating laboratories with those from the central laboratory found that the results were very similar (Figures 1 and 2). The differences between the Etest and MicroScan results from both the participating laboratories and the central laboratory for both gram-positive and gram-negative isolates were comparable. We concluded that the results from the participating laboratories were comparable to the results obtained in the central laboratory, whether the Etest or the MicroScan microdilution method was used. Therefore, the results of the larger database derived from the participating laboratories have been analyzed. The reference quality control strains also yielded results within the expected range (data not shown). Table I presents a survey of the susceptibility results for cefepime, shown as cumulative percentages of susceptible strains (only those species with 220 strains are shown) at each MIC value tested by Etest and by MicroScan at the participating laboratories. Comparative data for the antimicrobials tested by the two methods in the participant laboratories are shown in Tables II and III. These MIC values show that there are populations of bacteria that are very susceptible and others that are very resistant to all the antimicrobials tested. These data show that the activity of the antimicrobials tested was generally much greater for gram-negative than for gram-posi-

WI

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tive species. This was largely due to the inclusion of methicillin-resistant staphylococci and enterococci isolates, which were largely resistant to these agents. For methicillin-susceptible staphylococci, 95-100% of the isolates were susceptible to cefepime. The activity of cefepime (Table I) against species of Enterobacteriaceae was 290% (except for the microdilution result with E. cloacae, which was 88.9%) and against P. aeruginosa was 78.3-82.5%, depending on the method. The activity of cefepime against S. aureus correlated with the susceptibility of these isolates to methicillin-98% of methicillin-susceptible strains were susceptible to cefepime as compared to 14.9-20.6% of methicillin-resistant strains. Results were similar for S. epidermidis-100% of methicillin-susceptible isolates were susceptible to cefepime but only 49.2-52.6% of methicillin-resistant isolates were susceptible to cefepime. Very few enterococci tested were susceptible to cefepime, which supports the conclusion that the enterococci are resistant to the cephalosporins as a class. The range of MI&,, and MI&, values and susceptibilities” for both the Etest and MicroScan methods used by the participating laboratories for all the antimicrobials and species tested are shown in Table II and Table III. However, of the eight drugs studied, only cefepime, ceftazidime, ceftriaxone, ciprofloxacin, and imipenem were tested by both methods, because the other three drugs were not available with the Etest at th.e time this study was done. Therefore, neither the participant nor the central lab could test cefotaxime, gentamicin, or piperacillin by the Etest; they were tested in both by microdilution.

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Figure 1. Cumulative percentage of all gram-negative isolates (n = 8,165) susceptible to cefepime when tested by Etest (6,005) and by MicroScan (2,160) in the participating (Part.) and central (Cent.1 laboratories. (The central laboratory was the authors’.:’ S = susceptible (MIC 58 &mL); I = intermediate (MIC = 16 pg/mL); and R = resistant (MIC ~32 &mL).

SYMPOSIUM ON ANTIMICROBIAL

When the percentages of species susceptible to the five antimicrobials tested by both methods were averaged for all isolates using both central and participant laboratory data (Table IV ), the order of activity was imipenem (90.3%) > ciprofloxacin (82.9%) > cefepime (81.5%) > ceftazidime (68.9%) > ceftriaxone (68.5%). The order of activity for gram-positive isolates was similar, except for a reversal of positions for ceftazidime and ceftriaxone. The order of activity for gram-negative isolates was somewhat different-imipenem (95.5%) > cefepime (93.1%) > ciprofloxacin (92.1%) > ceftazidime (89.2%) > ceftriaxone (75.5%). The large difference between ceftazidime and ceftriaxone for the gramnegative organisms reflects the greater activity of ceftazidime against Pseudomonas. Since one of the attributes of cefepime is its stability in the presence of Bush group 1 ,&lactamases, the activity of cefepime against species likely to produce these enzymes merits special attention. When all the susceptibility data for both methods were averaged (Table IV), 95.9% of the E. cloacae isolates were susceptible to cefepime, compared with approximately 65% to ceftazidime, ceftriaxone, and cefotaxime (only Micro&an data were available for cefotaxime). The data are similar for Enterobacter aerogenes and Citrobacter freundii, the other species most likely to produce group 1 P-lactamases. Enterobacteriaceae species other than E. cloacae, E. aerogenes, and C. freundii generally showed >90% susceptibility to all agents tested; the exception being the 87.3% of Serratia marcescens that were susceptible to ciprofloxacin (using the Etest method). Using the mean

Figure 2. Cumulative percentage of all gram-positive isolates (n = 4.409) susceptibie to cefepime when tested by Etest (3,348) and by MicroScan (1,061) in the participating (Part.) and central (Cent.) laboratories. (The central laboratory was the authors’.) S = susceptible (MIC s8 &mL); I = intermediate (MIC = 16 &mL); and R = resistant (MIC 232 pg/mL). These data include methicillin-resistant S. aureus (MRSA), methicillin-resistant S. epidermidis (MRSE), and enterococcal species, all of which are considered a priori to be resistant to cefepime and other cephalosporins.

THERAPY/lHORNSBERRY

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susceptibility values for both tests (Tables II, III), we found that imipenem had the greatest activity against P. aeruginosa isolates (87.4%)) followed by ceftazidime (84.4%)) ciprofloxacin (810.6%)) cefepime (80.4%)) gentamicin (80.1%)) piperacillin (71.9%), ceftriaxone ( 16.9%)) and cefotaxime ( 12.0%). Cefotaxime, gentamicin, and piperacillin were tested only by MicroScan. The activity of the antimicrobials tested in this study against S. aureus was essentially dependent on methicillin susceptibility-most methicillinsusceptible strains being susceptible to these antimicrobials (except for piperacillin, which was inactivated by the P-lactamases produced by most isolates) and most MRSA being resistant. However, some strains of MRSA were susceptible to virtually all the antimicrobials. There were also some strains tested in the central laboratory that had MIC values of 0.5-l pg/mL, but these were strains that were hyperproducers of P-lactamases and were not intrinsically methicillin-resistant (data not shown). Although we could not be certain these inconsistently low MIC values from MRSA from the participant laboratories were correct, we chose not to delete any of these data arbitrarily. However, it is likely that these strains were not methicillin resistant. In spite of this, most of the data were consistent with MRSA, and the MI& and MICeo values were those that would be expected with MRSA, i.e., >64 pg/mL (Tables II, III). Overall, methicillin resistance in S. aureus was approximately 18%, and this is consistent with other national studies we have done (unpublished data).

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Isuppl 64

6A-29s

i

!

(all)

25

65

a9

41

38 121

60

135

541

214

272 308

258 0.0

0.0 0.0

0.5

0.2

0.7

0.0

0.0 0.5

87 106

53

0.0

357

97C

0.0

487

1435

3348

:;: l,C;;

6.6 0.3 0.8 2.9 1.9 0.0 0.1 0.0 0.6

2.6 3.7 7.4 1.8

Etes

0.0

0.0 0.0

0.0

0.0

0.0

0.0

1.1 0.0

C.0

2.7 0.2

64.8 44.0 42.5 19.3 40.0 12.9 0.0 0.0

28.4 62.5 41.1 58.9

Micr

0.4

0.4 0.0

0.5

0.4

0.7

0.0

0.0 0.5

1.7

0.0 1.7

0.0

0.0

0.0

0.0

1.1 0.0

0.0

0.2

C.0

6.0

1.5

77.8 84.3 52.5 45.9 48.6 40.0 0.3 0.0

41.4 85.3 58.7 79.1

Micr

0.1

41.8 2.5 30.8 20.7 19.8 1.5 0.4 0.8

17.7 26.7 49.2 28.0

Etes

1.6

0.4 0.0

0.5

0.4

0.7

0.0

0.0 0.5

0.0

0.2

2.7

75.8 38.4 54.9 54.2 59.0 31.4 6.7 1.6

35.2 53.2 82.3 68.2

Etes

47.7 97.2 70.5 88.7

Etes

1.7

1.6

1.7

1.9

0.7 0.3

8.9

5.0

0.7

5.7

0.3 2.4

0.2

6.8 0.5

1.7

0.0 1.7

17.1

9.0

0.0

48.0

1.1 14.2

0.6

10.1 0.8

87.0 94.8 75.0 69.6 80.0 77.1 2.7 0.0

50.5 96.0 Jo.4 89.7

Micr

1.9

1.8 0.3

53.3

25.1

1.5

69.8

0.3 21.5

1.1

94.5 97.5 85.0 76.4 91.5 93.8 14.6 4.1 12.8 1.3

53.2 75.7 98.7 93.3

Etes

1.7

0.0 1.7

68.3

33.7

3.1

68.0

1.1 23.6

10.6

17.9 8.2

92.6 97.0 87.5 73.3 84.3 84.3 9.6 4.0

55.3 73.7 96.7 91.6

Micr

by Participating 1

3.5

;:“d

79.0

39.2

5.2

94.3

3.2 30.2

21.6

24.1 17.7

98.9 98.9 94.7 85.4 95.8 96.9 48.6 19.5

62.7 99.2 84.3 96.1

Etes

1.7

10.5 1.7

87.8

47.2

6.2

80.0

3.4 31.1

78.7

94.4 97.8 92.5 83.0 90.0 87.1 50.0 la.C 47.4 63.4

71.3 98.2 83.0 93.5

Micr

6.2

33.1 3.6

93.9

60.1

24.4

98.1

8.0 45.4

92.8

100 99.7 97.7 92.7 97.6 96.9 64.6 37.4 55.5 72.8

77.1 99.4 89.1 98.2

4

3.3

la.4 3.3

92.7

53.9

30.8

96.0

lC.3 51.9

96.9

58.8 79.5

963 985 92.5 86.7 90.0 88.6 63.7 400

77.7 98.6 87.0 94.7

8.5

56.3 11.4

95.8

73.8

52.6

100

20.6 65.9

98.0

63.5 79.9

loo 99.7 98.5 98.3 97.6 97.4 78.3 50.4

82.2 99.5 92.7 99.0

10.0

36.8 4.1

95.1

62.9

49.2

100

14.9 64.2

98.0

62.8 81.1

98.1 99.3 95.0 88.9 90.0 92.9 82.5 56.0

82.1 98.7 91.7 95.4

13.6

67.3 la.8

97.7

80.8

77.0

100

29.3 82.9

99.!

too 99.7 99.2 99.1 99.1 97.9 89.6 60.2 68.7 82.6

85.8 95.4 99.7 99.5

13.3

52.6 9.1

95.1

71.9

72.3

100

17.2 80.2

98.3

98.1 100 97.5 92.6 92.9 95.7 94.8 72.C 66.8 81.9

85.9 99.5 95.3 96.2

27.9

75.0 35.4

99.1

86.0

83.7

100

31.8 88.8

99.5

loo 99.7 99.2 99.1 99.5 98.5 95.1 71.5 74.0 83.6

88.8 99.8 97.1 99.9

40.0

68.4 41.3

95.1

80.9

86.2

100

31.0 88.7

98.3

98.1 100 97.5 96.3 94.3 97.1 97.8 86.0 76.2 84.4

90.5 99.7 97.5 97.3

Using the Etest (Etes) and a Microdilution 8 16 32 Etes Micr Etes Micr Etes Micr Etes Micr

Laboratories 2

tested was 64 @/mL, the remarnrng organisms had MIC values ;-64; e.g., 9.5% of all organisms had MlCs of >64 &mL.

0.0 1.7

0.0

0.0

0.0

4.0

1.1 0.9

0.6

0.8

7.2

85.2 89.0 94.0 94.8 67.5 69.9 65.9 68.5 72.9 82.5 67.1 87.1 0.5 2.3 0.C 3.3

47.9 94.9 68.0 88.2

0.4 0.3

2.3

1.7

0.7

0.0

0.0 0.5

0.2

0.4

5.6

81.3 90.6 62.4 62.7 6’8.4 76.8 1.2 3.3

44.5 93.7 66.3 82.1

Micr

as Determined 0.5

0.0 1.7

0.0

0.0

0.0

0.0

1.1 0.0

0.0

0.4

6.5

al.5 91.8 65.0 60.7 61.4 60.0 0.5 0.0

0.25 Etes

Isolates,

45.8 92.8 65.1 84.4

Micr

* The microdlluhon trays were prepared by MuoScan (Sacramento, CA). ’ Mln~mum lnhlbltory concentration (MIC) values are in &ml. Smce the highest concentrabon f Sk;cfphble, ;e;;;:an: (ddkences represent the percen: in:ermedia:e~. b Methlclllin data not avaIlable on all strains. ‘I Enterococcl that were not speclated

1

1

54 134 40 135 70 70 366 50 1061

3221 2160 769 263

9353 6005 2131 7;:

362 133 343

Micr

Susceptibility to Cefepime of Bacterial Quantity 0.03’ 0.06 0.12

Etes

Percent

P. aerugrnosa A. anrtratus (Gram positive [all) S. aureus (all1 S. aureus, methrcill~n susceptible S. aureus, methicillin resrstant S. epidermidis tall) S. eprdermrdis, methicillin suscephblel S. epidermidis methrcillrn resistant Staphylococcus coagulase negatrve tall) Staphylococcus, coagulase negative, methicillrn susceptrble5, Staphylococcus, coagulase negative, methicillm resistant*, E. faecahs Enterococcus specres’r

Y. oxytoca P. mrrabrlrs C. freundii E. cloacae E. S. aerogenes marcescens

Y. pneumoniae

;,r;;;negative

;roup/Species VI organisms

Cumulative

rABLE I

42.2

80.1 50.3

99.5

88.9

86.7

71.7

84.2 66.9

97.6

89.9

93.8

10G

44.8 95.3

34.4 90.7 100

99.7

98.1 100 97.5 100 97.1 97.1 99.2 92.0 84.4 87.9

94.1 99.7 98.8 97.7

99.6

loo 99.7 100 99.7 100 98.5 96.8 90.2 78.0 84.4

91.1 99.9 98.4 99.9

8.5

56.3 11.4

95.8

73.8

52.6

100

20.6 65.9

980

100 99.7 98.5 98.3 97.6 97.4 78.3 50.4 63.5 79.9

82.2 99.5 92.7 99.0

10.0

36.8 4.1

95.1

62.9

49.2

100

14.9 64.2

98.0

98.1 99.3 95.0 88.9 90.0 92.9 82.5 56.0 62.8 al.1

82.1 98.7 91.7 95.4

Method (MicroScan, 64i St& Etes Micr Etes Micr

1.9 ;:;

1.7

0.0

4.9

86.5 86.7

32.7 47.4 al.1 90.9

2.3

19.2 28.1

23.0 27.7

0.0

70.7 82.8 17.0 19.8

1.0

0.8 7.4 1.0 7.1 2.1 4.2 10.4 5.2 39.8 28.0 31.3 33.1 17.3 18.1

0.0 ;:;

14.2 14.1 4.6 4.6 0.; ;I;

Etes Micr

Rest

Micr)*

rABLE II Summary of Susceptibility Wimicrobial

411 organisms Cefeplme Ceftazidime Ceftriaxone Ciprofloxacin lmipenem 411 Gram positive organisms Cefepime Ceftazidlme Ceftriaxone Ciprofloxacin lmlpenem 411 Gram negative organisms Cefepime Ceftazidime Ceftriaxone Ciprofloxacin lmipenem kinetobacter anitratus Cefepime Ceftazldime Ceftrlaxone Ciprofloxacin lmlpenem Citrobacter freundii Cefepime Ceftazidime Ceftriaxone Clprofloxacin lmipenem Enterobacter aerogenes Cefeplme Ceftazidime Ceftrlaxone Clprofloxacln lmipenem Enterobacter cloacae Cefepime Ceftazidime Ceftriaxone Ciprofloxacin lmipenem Escherichia coli Cefepime Ceftazidime Ceftriaxone Ciprofloxacln lmipenem Klebsiella oxytoca Cefepime Ceftazidime Ceftriaxone Ciprofloxacln lmipenem Kfebsiella pneumoniae Cefepime Ceftazldlme Ceftrlaxone Ciprofloxacin lmipenem Pseudomonas aeruginosa Cefepime Ceftazidime Ceftriaxone Ciprofloxacin lmipenem Proteus mirabilis Cefepime Ceftaztdime Ceftriaxone Ciprofloxacin lmipenem

to Selected Antimicrobials

No. Isolates

MIGo

1

9,353 8,641 8,766 8,769 8,776

2 2 0.25 0.5

3,348 3,059 3,106 3,105

4 32 8 0.5

3,109

0.12

6,005 5,582 5,660 5,664 5,667

0.12 0.5 0.12 0.06 0.5

123 112 112 112 112

a 16 64 0.5 0.5

133 127 128

0.12

129

0.12

129

0.5

212 187

0.12 0.5 0.25 0.06

198 198 198 343 315 324 324 324 2,131 2,005 2,030 2,030 2,030 91

1 0.5

1 0.12 1 0.5 0.03 0.5 0.12 0.25 0.06 0.03 0.25

Obtained by the Participating MI&,,

Geo Mean’

64 >256 >256 32 8 >256 >256 >256 >32 >32

>256

1 4 64 >256 >256 >32 4

1 4 2 0.25 0.5

82.2 62.3 66.9 81.8 89.8

0.25 1 0.5 0.06 0.5

% Rest

3.6

14.2 25.8 22.9 14.1 a.7

11.9 10.2 4.1 1.5 5.2

14.9

29.5

53.7 63.7 82.9

11.3 7.9 1.3

92.7 88.3 74.1

2.7 2.3 9.6 2.0 1.6

16.3

39.8 39.3 55.3 41.1 3.5

91.8 93.6

31.3 55.6 35.0 28.4 15.8 4.6 9.4 6.2 4.8

16 32 64 2

50.4 47.3 6.3 57.1

1

93.8

9.8 13.4 38.4 1.8 2.7

2

0.25 4 4

98.5 63.8 62.5

0.8 0.0 4.7

0.7 36.2 32.8

1 1

0.12 0.5

91.5 100

1.6 0.0

6.9 0.0

1 128 128 0.5 2

0.25 2

97.6 72.2

1.4 2.7

25.1

4

>256 >256

>256 >256 0.25 2 0.25 1 0.25 0.06 0.5 1 4 4

1

71.2 94.9

10.1 1.0

18.7 4.1

1

99.0

0.5

0.5

0.25 4 4 0.06 0.5

98.3 65.7 65.4 96.9 97.5

0.9 1.6 2.8 0.0 1.2

0.8 32.7 31.8 3.1 1.3

0.12 0.5 0.06 0.03 0.25

99.5 98.6 99.0 99.2 99.7

0.2 0.3 0.2 0.2

0.3

0.12 0.5 0.12 0.06 0.5

100 94.1

0.0 1.2

95.3 94.1 98.8

2.4 0.0 0.0

4.7 2.3 5.9 1.2

0.4 1.2 1.6 1.4 0.0

0.6 5.3 1.7 5.4 0.4

11.3 5.2 39.0 5.4 5.1

10.4 12.4 49.7 12.7 12.2

736 679 690 690 690

0.12 0.5 0.12 0.06 0.25

1

0.12

99.0

2 0.5 0.5 0.5

0.5 0.12 0.12 0.25

93.5 96.7 93.2 99.6

1,072 1,001 1,002 1,004

4 2 32 0.25 2

32 32 >256 4 32

362 331 339 339 339

0.25 0.25 0.03 0.06 0.5

0.25 0.5 0.5 0.12 4

0.25 0.5

June 24.

1.0

0.06

85 85 85

994

% InF

63.5

0.12 0.25 0.12 0.03 0.5

a5

Using the Etes,t Method

% sus+

a 64 16 2 0.5

8 16

Laboratories

4 4 64 0.5 4

81.9 82.7 99.7 99.4 97.3 97.6

1

93.5

1996 The American

0.1

78.3 82.4 11.3

0.25 0.25 0.06 0.06

Journal

of Medicine@

1.1 0.8 0.6 0.2

0.0

0.0 0.3 1.2 0.9 3.8

Volume

100 kuppl

0.3 0.3 1.5 1.5 2.7

6A)

6A-31S

TABLE

II (Continued)

Antimicrobial

No. Isolates MC% Serratia marcescens Cefepime 194 0.25 Ceftazidime 173 0.5 Ceftriaxone 181 0.25 Ciprofloxacin 181 0.25 lmipenem 181 0.5 Enterococcus faecalis Cefepime 308 64 Ceftazidime 253 >256 Ceftriaxone 255 ~256 Ciprofloxacin 257 2 lmipenem 257 2 Enterococcus species Cefepime 258 2256 Ceftazidime 232 >256 Ceftriaxone 239 >256 Ciprofloxacin 240 2 lmipenem 241 2 Staphylococcus aureus (all) Cefepime 1,435 4 Ceftazidime 1,329 16 Ceftriaxone 1,348 a Ciprofloxacin 1,347 0.5 lmipenem 1,347 0.06 Staphylococcus auraus, methicillin susceptible Cefepime 970 4 Ceftazidime 917 16 Ceftriaxone 920 a Ciprofloxacin 919 0.5 lmipenem 919 0.06 Staphylococcus aureus, methicillin resistant Cefepime 311 >256 Ceftazidime 272 2256 Ceftriaxone 273 2256 Ciprofloxacin 273 >32 lmipenem 273 >32 Staphylococci, coagulase negative (all] Cefeprme 541 4 Ceftazidime 496 32 Ceftriaxone 511 16 Ciprofloxactn 509 0.25 lmipenem 511 0.25 Staphylococci, coagulase negative, methiclllln susceptible Cefepime 214 1 Ceftazidime 193 16 Ceftriaxone 194 4 Ciprofloxacln 194 0.25 lmipenem 194 0.06 Staphylococci, coagulase negative, methicillin resistant Cefepime 272 8 Ceftazidime 253 64 Ceftriaxone 255 64 Ciprofloxacrn 254 2 imipenem 256 I Staphylococcus epidermidis (all) Cefepime 205 a Ceftazidime 185 32 Ceftriaxone 185 32 Ciprofloxacin 184 0.5 lmipenem 185 0.5 Staphylococcus epidermidis, methicillin susceptible Cefepime 53 1 Ceftazidime 49 8 Ceftriaxone 49 2 Ciprofloxacin 49 0.25 lmipenem 49 0.06 Staphylococcus epidermldls, methicillin resistant Cefepime 135 a Ceftazidime 124 64 Ceftriaxone 124 64 Ciprofloxacin 123 8 lmipenem 124 16

MICW

Geo Mean *

1 2 2 2 2

0.25 0.5 0.5 0.25 1

% lnt+

97.4 94.2 93.4 87.3 98.9

0.5 0.6 2.2 5.5 0.0

2.1 5.2 4.4 7.2 1.1

% Rest

>256 r256 >256 >32 a

128 256 128 4 2

11.4 2.4 18.4 32.7 89.5

7.5 3.6 5.5 30.0 4.3

81.1 94.0 76.1 37.3 6.2

>256 >256 >256 >32

128 256 256 4 2

8.5 5.2 11.3 28.7 88.8

5.0 1.7 5.4 26.7 2.9

86.5 93.1 83.3 44.6 8.3

732

8 32 16 1 0.25

79.9 7.5 75.1 76.2 86.2

2.8 50.8 5.4 1.9 0.6

17.3 41.7 19.5 21.9 13.2

4 32 a 0.1:

4 16 8 :::6

98.0 a.7 96.0 93.7 99.8

1.0 65.0 3.6 2.0 0.1

1.0 26.3 0.4 4.3 0.1

20.6 1.1 7.3 16.5 38.8

8.7 5.5 8.4 1.5 2.2

70.7 93.4 84.3 82.0 59.0

8 32 16 k.5

73.8 21.2 41.1 67.6 75.7

7.0 21.2 28.6 2.0 1.0

19.2 57.6 30.3 30.4 23.3

2 16 4 0.5 0.06

95.8 43.0 83.0 91.8 97.4

1.9 34.7 13.4 2.1 0.0

2.3 22.3 3.6 6.1 2.6

>256 >256 >256 >32 >32

16 64 64 4 4

56.3 3.2 a.2 48.4 59.0

11.0 11.5 40.0 1.6 1.6

32.7 85.3 51.8 50.0 39.4

64 r256 >256 r32 >32

8 64 32 2 2

65.9 20.0 28.6 59.2 62.2

17.1 14.1 25.4 1.6 0.5

17.0 65.9 46.0 39.2 37.3

100 63.3 93.9 93.9 100

0.0 28.6 6.1 0.0 0.0

0.0 8.1 0.0 6.1 0.0

52.6 2.4 2.4 46.3 46.8

24.4 8.1 33.1 1.6 0.8

23.0 89.5 64.5 52.1 52.4

a >256 >256 >256 >32

>256 >256 >256 >32

128 256 256 32

732 256 >256 >256 >32 >32 4 32 16 1 0.12

a

2 16 a 0.5 0.12 2256 >256 >256 232 >32

1 8 2 0.25 0.06 1:: 64 4 a

” Geometric mean minrmum inhibitory concentration (MIC). r Percent susceptible, percent intermediate, and percent resistant using NCCLS breakpoints.

6A-32s

% Susf

June 24, 1996 The American Journal of Medicine@ Volume 100 (suppl6Al

rABLE

III Summary

hntimicrobial

of Susceptibility No. Isolates

&II organisms Cefepime Cefotaxlme Ceftazidime Ceftrlaxone Ciprofloxacin lmlpenem Gentamun Plperaollln 411 Gram positive organisms Cefepime Cefotaxime Ceftazldime Ceftnaxone Ciprofloxacln lmlpenem Gentamicrn Piperacillin RII Gram negative organisms Cefeptme Cefotaxime Ceftazidime Ceftriaxone Ciprotloxacin lmlpenem Gentamicin Piperacillkn Acinetobacter anitratus Cefepime Cefotaxime Ceftazldime Ceftrlaxone Clprofloxacln lmipenem Gentamicin Piperactllln Citrobacter freundii Cefepime Cefotaxime Ceftazidime Ceftriaxone Ciprofloxacin lmipenem Gentamicln Piperacillin Enterobacter aerogenes Cefepime Cefotaxime Ceftazidime Ceftriaxone Clprofloxacin lmlpenem Gentamicin Plperacillin Enterobacter cloacae Cefepime Cefotaxime Ceftazidime Ceftriaxone Clprofloxacin lmipenem Gentamlcin Plperacillin Escherichia coli Cefeplme Cefotaxime Ceftazidime Ceftriaxone Clprofloxacin lmipenem Gentamicln Piperacllitn

to Selected Antimicrobials Using the MicroScan MICm

MlCw

3,221 3,227 3,255 3,218 3,227 3,256 3,267 3,254

0.5 1 1 1 0.12 0.25 1 4

32 >64 >64 >64 8 4 16 512

1,061 1,057 1,055 1,055 1,061 1,049 1,061 1,059

4 2 16 2 0.5 0.03 1 8

2,160 2,170 2,200 2,163 2,166 2,207 2,206 2,195

-

Obtained Method

by the Participating

Geo Mean’

Laboratories

% Sus’

% Int’

% ResT

0.5 1 2 1 0.25 0.25 2 16

82.1 71.2 76.3 72.0 85.1 90.4 81.3 64.0

3.8 11.2 5.0 9.1 2.7 2.0 4.4 12.7

14 1 17.6 18.7 18.9 12.2 7.6 14.3 23.3

~64 >64 >64 >64 >32 32 > 32 256

8 4 16 8 1 0.25 2 a

62.8 65.4 49.8 62.1 71.7 78.8 63.3 60.9

4.1 5.4 9.7 7.2 4.3 4.8 7.9 19.1

33.1 29.2 40.5 30.7 24.0 16.4 28.8 20.0

0.06 0.06 0.25 0.06 0.03 0.25 1 4

8 64 16 64 1 2 8 2512

0.25 0.5 0.5 0.5 0.06 0.5 1 16

91.7 74.1 89.1 76.8 91.7 95.8 89.9 65.4

3.7 14.0 2.8 10.0 1.8 0.7 2.7 9.6

4.6 11.9 8.1 13.2 6.5 3.5 74 25 0

50 50 49 50 50 50 50 50

8 32 8 16 0.5 0.25 2 32

64 >64 >64 >64 >32 2 >32 r512

8 32 16 32 1 0.5 8 64

56.0 20.0 59.2 32.0 60.0 92.0 56.0 42.0

16.0 38.0 4.1 28.0 6.0 2.0 6.0 18.0

28 0 42.0 36.7 40.0 34.0 6.0 38.0 40.0

40 40 40 40 40 40 40 40

0.06 0.25 0.5 0.25 0.03 0.5 0.5 8

2 64 >64 64 0.5 1 2 256

0.12 1 4 1 0.06 0.5 0.5 16

95.0 65.0 65.0 67.5 95.0 97.5 97.5 55.0

2.5 22.5 2.5 17.5 0.00 2.5 0.00 17.5

2.5 12 5 32.5 15.0 5.0 0.00 2.5 27.5

70 71 72 70 73 73 73 73

0.12 0.25 0.5 0.12 0.03 1 0.5 4

2 32 64 32 1 2 2 256

0.12 0.5 1 1 0.06 1 1 16

90.0 71.8 68.1 77.1 91.8 95.9 93.2 64.4

2.9 19.7 9.7 15.7 0.00 2.7 0.00 19.2

7.1 8.5 22.2 7.2 8.2 1.4 6.8 16.4

135 137 137 137 137 137 137 137

0.12 0.5 0.5 0.25 0.03 0.5 0.5 4

16 >64 >64 264 0.5 2 4 512

0.25 2 2 1 0.06 0.5 1 16

88.9 65.0 66.4 65.0 95.6 97.1 92.0 62.8

3.7 5.8 2.9 8.0 2.2 0.7 1.5 8.8

7.4 29.2 30 7 27.0 2.2 2.2 6.5 28.4

769 772 792 770 764 793 792 788

0.03 0.06 0.12 0.03 0.015 0.12 1 2

0.06 0.06 0.25 0.06 0.03 0.12 1 16

98.7 98.2 97.7 98.2 98.3 99.4 96.3 66.4

0.8 1.2 0.9 0.8 0.1 0.1 0.6 2.3

0.5 06 1.4 1.0 1.6 0.5 3.1 31.3

0.12 0.12 0.5 0.06 0.03 0.25 2 >512

June 24,

1996

The American

Journal

of Medune@

Volume

100 (suppl

6A)

6A-33s

TABLE

III (Continued)

Antimicrobial KlebsieMa

No. Isolates

Cefepime Cefotaxime Ceftazidime Ceftriaxone Ciprofloxacin lmipenem Gentamicin

54 54 55 54 54 55

Piperacillin Klebsiella pneumoniae Cefepime Cefotaxime Ceftazldime Ceftriaxone Ciprofloxacin lmipenem Gentamicln Piperacillin Pseudomonas aeruginosa Cefepime Cefotaxime Ceftazidime Ceftriaxone Ciprofloxacin lmipenem Gentamicln Plperacillin Proteus mirabilis Cefepime Cefotaxime Ceftazidime Ceftriaxone Ciprofloxacin lmipenem Gentamlcin Piperacillin Serratia marcescens Cefepime Cefotaxime Ceftazidime Ceftriaxone Ciprofloxacin lmipenem Gentamicin Piperacillin Enterococcus faecalis Cefepime Cefotaxime Ceftazidime Ceftriaxone Ciprofloxacin lmipenem Gentamicin Piperacillin Enterococcus species Cefepime Cefotaxime Ceftazidime Ceftriaxone Ciprofloxacin lmipenem Gentamlcin Piperacillin Staphylococcus aureus Cefepime Cefotaxime Ceftazidime Ceftriaxone Ciprofloxacln lmlpenem Gentamicin Piperacillin

6A-34s

MC50

MlC~

Geo Mean’

1

0.06 0.06 0.25 0.12 0.03 0.25 0.5 32

% Sus’

% lnt+

% Res’

oxytoca

June

24, 1996

0.03 0.03 0.12 0.03 0.015 0.25 0.5 16

E 263 264 272 263 270 272 272 271

0.03 0.06 0.12 0.03 0.03 0.25 0.5 16

366 367 367 366 366 367 367 367

2 32 2 32 0.25

134 135 135 135 133 139 139 134

0.06 0.03 0.06 0.03 0.03 2

8

1 8 0.12 1

1 2512

1 2 2 4 0.5

1 1 512 16 264 16 ~-64 8 4 8 64

1 4 4

1 0.5

70 71 71 69 71 71 71 70

0.12 0.5 0.25 0.25 0.12

8 32 8 16

1 1

2

121

60 59 59 59 60 59 60 59

82.5

5.2 33.2 9.5 39.6 15.3 5.7 9.3

92.1

4 8

80.1 71.9

0.06 0.03 0.06 0.03 0.03 2 1

99.3 97.8 99.3 97.8 99.2 96.4 93.5 90.3

0.7 1.5 0.0 0.7 0.0 0.7 0.0 1.5

0.0 0.7 0.7 1.5 0.8 2.9 6.5 8.2

92.9 81.7 90.1 88.4 90.1 95.8 88.7 74.3

2.9 9.9 4.2 5.8 0.0 0.0 0.0 14.3

4.2 8.4 5.7 5.8 9.9 4.2 11.3 11.4

4.1 6.8 4.3 6.0 67.8 95.0

5.0 5.1 0.9 3.4 12.4 1.7

90.9 88.1

9.1

18.2

0.5 16 2

4

1.9 0.0

1

1

>32

98.1 100 100

3.7 1.8 3.7

12.3 54.8 4.1 38.0 5.5 2.2 10.6 11.2

64 64 >64 64

1

90.7 98.2 90.7

12.0

64 64 >64 >64 2 0.5 16 2

>64 ~-64 >64 >64 >32

0.5 16 2

4

8

4

1

3.8 3.0 5.1 3.0 4.1 1.6 7.0 24.7

1 1

232

64 ~-64 >64 >64

0.8 2.3 1.5 2.7 0.7 0.4 0.4 20.7

0.5 0.5 0.25

1

0.5 16 2

95.4 94.7 93.4 94.3 95.2 98.9 92.6 54.6

1

>64 >64 ~-64 464 132

1

0.06 0.12 0.25 0.06 0.06 0.25 0.5 32

0.25

128

64 >64 >64 >64

117 117 117 121 121 121 121

0.0 25.5

1

16

4

50.9

4 32 0.5

1

1.9

0.0 5.6 0.0 5.6 0.0 0.0 0.0 23.6

216

0.12 0.03 0.5 0.03 0.03 4 4 8

98.1

86.4 22.4 79.2

16.9

94.8 90.6

19.8

95.0

1.7

3.3 72.7 3.3

10.0 10.2 3.4 10.2 70.0 96.6 11.7 96.6

3.3 3.4 5.1 5.1 11.7 0.0 25.0 3.4

86.7 86.4 91.5 84.7 18.3 3.4 63.3 0.0

81.1 83.0 70.1 82.5 78.2 80.5 87.9 40.7

0.8 3.1 8.7 2.1 1.6 2.3 0.6 28.7

18.1 13.9

(all) 487 487 485 486 486 478 488 487

The American

2

>64 >64 >64 >64 >32 32 32 256

1 8 2 0.5 0.015 0.5 32

Journal

of Medicine@

Volume

100

4 2 16 4

1 0.06 3:

(suppl

6A)

21.2 15.4 20.2 17.2 11.5 30.6

TABLE

III (Continued)

Antimicrobial Staphylococcus Cefepime Cefotaxime Ceftazidime Ceftriaxone Ciprofloxacin lmipenem Gentamicin Piperacillin Staphylococcus Cefepime Cefotaxime Ceftazldime Ceftriaxone Ciprofloxacin lmlpenem Gentamicin Piperacillin Staphylococci, Cefepime Cefotaxime Ceftazidime Ceftriaxone Ciprofloxacin lmipenem Gentamicin Piperacillin Staphylococci, Cefepime Cefotaxime Ceftazldime Ceftriaxone Ciprofloxacin lmipenem Gentamicin Piperacillin Staphylococci, Cefepime Cefotaxime Ceftazidime Ceftriaxone Ciprofloxacin lmipenem Gentamicin Piperacillin Staphylococcus Cefepime Cefotaxime Ceftazldime Ceftriaxone Ciprofloxacin lmipenem Gentamicin Piperacillin Staphylococcus Cefepime Cefotaxime Ceftazidime Ceftriaxone Ciprofloxacin lmipenem Gentamicin Piperacillin Staphylococcus Cefepime Cefotaxime Ceftazldime Ceftriaxone Ciprofloxacin lmipenem Gentamicin Piperacillin

No. Isolates aureus.

methicillin 357

MICN, 2

358 357 356 358 347 358 356 aureus.

metbicillin

1 a 2 0.5 0.015 0.5 16 >64 r64 >64 >64 32 32

::

87 85 88 87

1

88 negative 89

128

% Sus’

4 4 16

8 0.5

89

0.12

88 88

0.25 a

negative, 41 i:

metbicillin

2

98.0

0.3

1.7

2 16 2 1 0.03 1 256

1 a i.5

98.3 86.8 98.9 94.1 98.6 96.9 50.0

0.6 10.1 0.0 1.4 0.6 0.3 27.5

1.1 3.1 1.1 4.5 0.8 2.8 22.5

14.9 22.1 2.4 19.5 12.9 12.5 54.0 6.8

2.3 15.1 2.4 10.3 3.5 9.1 1.1 34.1

82.8 62.8 95.2 70.2 83.6 78.4 44.9 59.1

a 4 16 8 1 0.5 0.5 a

62.9 66.3 40.4 58.4 64.0 61.8 67.0 61.4

9.0 10.1 22.5 14.6 1.1 12.4 5.7 25.0

28.1 23.6 37.1 27.0 34.9 25.8 27.3 13.6

1

95.1 95.1 73.2 95.1 90.2 90.2 87.8 85.4

0.0 0.0 22.0 0.0 0.0 2.4 0.0 9.8

4.9 4.9 4.8 4.9 9.8 7.4 12.2 4.8

0.015 0.5 16

>64 264 >64 >64 >32 232 >32 512

64 32 >64 64 32 16 a 128

>64 >64 >64 264 232 32 >32 128

susceptible

1 1

41 41 41 41 41 negative,

4 1:

:,

methicillin

38

38 38 37 37

epidermidis,

(all) 106 106 106 106 106 105 104 106 methicillin

methicillln

65 65 65 65 65 64 63 65

0.015 0.12

16

2

32

2 0.25 0.03 0.25 2

resistant

16 16 32 32 4 a 4 32

>64 >64 >64 >64 >32 32 >32 256

16 16 32 32 4 8 4 32

36.8 42.1 5.3 26.3 44.7 34.2 51.4 43.2

15.8 18.4 28.9 26.3 0.0 23.7 10.8 35.1

47.4 39.5 65.8 47.4 55.3 42.1 37.8 21.7

4 4

64 >64 64 >64 232 32 >32

8 4 16 8 2 1 2

8

128

8

64.2 68.9 28.3 56.6 55.7 55.2 51.9 62.3

16.0 17.0 23.6 27.4 0.9 16.2 4.8 22.6

19.8 14.1 48.1 16.0 43.4 28.6 43.3 15.1

1 0.5 4 1 0.25 0.015 0.25 2

4 4 32 8 4 4 16 128

1 0.5 8 1 0.5 0.03 0.5 2

100 100 72.0 92.0 84.0 96.0 84.0 88.0

0.0 0.0 16.0 8.0 0.0 4.0 4.0 0.0

0.0 0.0 12.0 0.0 16.0 0.0 12.0 12.0

49.2 53.8 7.7 38.5 43.1 35.9 38.1 47.7

23.1 27.7 26.2 40.0 1.5 23.4 4.8 35.4

27.7 18.5 66.1 21.5 55.4 40.7 57.1 16.9

16

8 0.5 4 1 susceptible

25 25 25 25 25 25 25 25 epidermidis,

4 1 1

h.25

38 38 38

epidermidis

x Res’

4

a

coagulase

% Int’

(all)

:; :;

coagulase

Geo Mean*

resistant

87

coagulase

MC,

susceptible

resistant

16 8 32 16 4 8 16 32

* Geometric mean minimum inhibitory concentration (MU. + Percent susceptible, percent intermediate, and percent resistant

64 >64 64 >64 >32 32 ~32 128

16 a 32 16 4 a a 16

using

NCCLS

June

24,

breakpoints.

1996 The American

Journal

of Medicine”

Volume

100

(SUPPI

6N

6A-35s

SYMPOSIUM ON ANTlMlCROBlAL

THERAPYflHORNSBERRY

AND YEE

TABLE IV Mean Percent Susceptible of the Etest (Two Results), MicroScan (Two Results), and the Two Methods Combined (Four Results) for All Organisms, All Gram Negative Organisms, All Gram Positive Organisms, and Enterobacter cloacae % Susceptible (Means) All Organisms All Gram Negative All Gram Positive Enterobacter cloacae Antimicrobial Agent E’ M M M M E/M E E/M E E/M E E/M Cefepime Ceftazidime Ceftriaxone Ciprofloxacin lmipenem Cefotaxime Gentamicin Piperacillin

82.0r 62.9 66.2 81.2 90.8 -

81.1 74.9 70.9 84.6 89.8 70.1 80.1 66.0

81.5 68.9 68.5 82.9 90.3 -

93.6 89.1 74.2 92.4 94.8 -

92.5 89.3 76.8 91.8 96.2 73.7 90.7 68.5

93.1 89.2 75.5 92.1 95.5 -

62.0 17.2 52.3 61.9 83.5 -

60.9 48.3 60.0 71.4 77.8 63.6 60.6 61.3

61.2 32.7 56.1 66.6 80.9 -

99.2 65.9 64.8 94.7 97.8 -

92.6 65.3 65.5 94.1 97.6 64.6 95.1 62.6

95.9 65.6 65.2 94.4 97.7 -

* E = Etest results; M = MicroScan results; E/M = combined results. + Mean percent susceptible (NCCLS breakpoints).

When the susceptibilities of all organisms to cefepime were compared according to the two methods, the results were very similar--82.0% (Etest) and 81.1% (MicroScan) of all isolates were susceptible; 93.6% (Etest) and 92.5% (MicroScan) for all gram-negative isolates and 62.0% (Etest) and 60.9% (MicroScan) susceptibility for all gram-positive isolates (Table IV). There were differences, however, in the percentage susceptible as determined by the two methods for some species, i.e., some staphylococci, enterococci, and Enterobacter spp. (Table I). In each of these groups, greater susceptibility (a lower MIC value) was obtained with the Etest. The results for cefepime with the Etest and the MicroScan methods are also shown graphically for all gram-negative isolates in Figure 1 and for all gram-positive isolates in Figure 2. Some differences between results obtained with the Etest and MicroScan were apparent. For gram-negative isolates, the most obvious differences were at the lower MIC values (<0.03-0.12 hg/mL), with the most divergent results occurring at MIC values of 10.03 hg/mL. The major differences between the two methods with the gram-positive isolates occurred at 2 pg/mL. The differences between the two methods were reproducible and could not be explained by data obtained with reference strains, since their MIC values were within the expected range. We conclude that the results with the two methods are essentially comparable, even though there were some sizable reproducible differences with gram-negative isolates tested at lower concentrations of cefepime (0.030.12 pg/mL).

curring pathogens in hospitalized patients. In rank order, other than S. pneumoniae, the 11 most frequently isolated organisms were E. coli, S. aureus, P. aeruginosa , coagulase-negative staphylococci, K. pneumoniae, enterococci, Proteus mirabilis, E. cloacae, E. aerogenes, S. marcescens, and C. freundii. The overall susceptibility to cefepime was 96.8% (average of data by both methods) for Entterobacteriaceae and 98% for methicillin-susceptible staphylococci; it was 82.6% for P. aeruginosa. None of the drugs tested demonstrated consistent activity against MRSA, and the enterococci were recognized as being resistant to all tested cephalosporins. S. pneumoniae from the United States were susceptible to cefepime, as determined in another study.z5 When all isolates were included, penicillinsusceptible, -relatively resistant, and -resistant strains (n = 162), the MICE0 and MI&, values for cefepime were 0.25 and 1.0 pg/mL; 95.1% of peniclllin-resistant strains (as judged by the oxacillin screen test) were susceptible to cefepime. One of the important attributes of cefepime and a major reason for designating it as a “fourth-generation” cephalosporin is its stability in the presence of Bush group 1 P-lactamases.‘~‘” Among the most frequently isolated species in the study, P. aeruginosa, E, cloacae, E. aerogenes, S. marcescens, and C. freundii are known to produce Bush group 1 ,&lactamases; in our experience, E. cloacae, E. aerogenes, and C. freundii are the species most likely to do so. Overall, 20-30% of these species are resistant to third-generation cephalosporins and probably produce group 1 ,&lactamases. Since Bush group 1 plactamases inactivate penicillins and cephalosporins but do not inactivate a fourth-generation cephalosporin, such as cefepime, one would expect the DISCUSSION third-generation cephalosporins to be less active The species found in this study were typical of against these organisms than cefepime. In this study, those expected in a surveillance study of usually oc- >95% of these three species (E. cloacae, E. aeroge6A-36s

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nes, and C. freundii) were susceptible to cefepime, whereas only 60-79% were susceptible to the thirdgeneration cephalosporins. Cefepime has activity similar to that of ceftazidime against P. aeruginosa, and both drugs have much greater activity than cefotaxime and ceftriaxone against this species. The increased activity of cefepime against E. cloacae when compared with third-generation cephalosporins is of clinical interest because this organism is being increasingly identified as the causative agent of severe systemic infections in hospitalized patients.23824 Approximately 35% of the E. cloacae isolates in this study were resistant to the three thirdgeneration cephalosporins-ceftazidime, ceftriaxone, and cefotaxime -whereas only 4% were resistant to cefepime. Only imipenem, ciprofloxacin, and gentamicin showed activity similar to that of cefepime (all had susceptibility rates >92% against isolates of E. cloacae [Table IV] ) . Similar findings of the increased activity of cefepime compared with other cephalosporins were noted for E. aerogenes and C. freundii isolates. One of the purposes of this study was to evaluate the activity of current hospital isolates to cefepime and comparative agents from each laboratory using one of two current methods of susceptibility testing and to compare the results of about 19% of the isolates with those of a central laboratory (the authors’) using both methods as a form of quality assurance. A comparison of the results obtained by the participating laboratories as a whole to the results from the central laboratory showed the results to be very comparable. The confirmation of the overall susceptibility results from the participant laboratories was obviously an important finding, but particularly important was that the differences between the two methods were duplicated in the central laboratory. We used both the broth microdilution method and the Etest method. One advantage of the Etest is its versatility; it can be used to determine the MIC of an antimicrobial that is not currently on one of the commercially available automated MIC systems. The comparability of the Etest results with those of the broth microdilution method support the use of the Etest for cefepime. The Bauer-Kirby disk diffusion method2’ may also be used.

CONCLUSION Antimicrobial susceptibility results obtained with two different MIC methods-microdilution and Etest-showed that most isolates of Enterobacteriaceae were susceptible to cefepime, exceeding the activity of ceftazidime, ceftriaxone, and cefotaxime. This improved activity is likely due to the greater activity of cefepime against species that produce

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Bush group 1 ,&lactamases (predominantly E. cloacue, E. aerogenes, and C. freundii) . In addition, the activity of cefepime against P. aeruginosn isolates was comparable to that of ceftazidime and greater than that of ceftriaxone or cefotaxime. Most methicillin-susceptible 5’. aureus species were susceptible to cefepime, but methicillin-resistant S. a?Lreus and enterococci were generally resistant. Overall, the most active antimicrobials in this study were imipenem, ciprofloxacin, and cefepime. Categorically, the results from the microdilution MIC and Etest method were similar.

REFERENCES 1. Kessler RE, Fung-Tome J. Susceptibility of bacterial isolates to 8-lactam antibiotics from U.S. clinical trials over a 5year period. Am J Med. 1996;1OOfsuppl6A):13S-19s. 2. Nikaido H, Liu W, Rosenberg EY. Outer membrane permealsility and plactamase stability of dipolar ionic cephalosporins containing methoxyimino sub stituents. Antimicrob Agents Chemother. 1990;34:337-342, 3. Fung-Tome J, Huczko E, Kolek B, et al. In vitro activities of Ncefepime alone and with amikacin against aminoglycosideresistant gram-negative bacteria. Antimicrob Agents Chemother. 1991;35:2652-2654, 4. Giamarellou H, Sahin A, Chryssauli Z. Comparative in vitro evaluation of BMY28142, a new broad-spectrum cephalosporin, versus other p-lactams against multiresistant gram-negative isolates, Drugs Exp C/in Res. 1987;13:149-153. 5. Uri JV, Burdash N, Bendas CM. The aminothiazol-oxyimino cephalosporin antibiotics with quaternary ammonium substituents at the 3position. Acta Micobiologica Hungarica. 1988;35:327-356. 6. Yoshimura F, Nikaido H. Diffusion of Dlactam antibiotics through the porin channels of Escherichia coli K-12. Antimicrob Agents Chemother. 1985;27:84. 7. Bellido F, Pechere JC, Hancock REW. Novel method for measurement of outer membrane permeability to new @-lactams in intact Enterobacter cloacae cells. Antimicrob Agents Chemother. 1991;35:68-72. 8. Hancock REW, Bellido F. Factors involved in the enhanced efficacy against gram-negative bacteria of fourth generation cephalosporins J Antimicrob Chemother. 1992;29fsuppl A):l-6. 9. Fuchs PC, Jones RN, Barry AL, Thornsberry C. Evaluation of the in vitro activity of BMY-28142, a new broad-spectrum cephalosporin. Antimicrob Agents Chemother. 1985;27:679-682. 10. Pucci MJ, BoiceSowek J, Kessler RE, Dougherty TJ. Comparison of cefe pime, cefpirome, and cefaclidine binding affinities for penicillin-binding proteins in Escherichia coli K-12 and Pseudomonas aeruginosa SC8329. Antimicrob Agents Chemother. 1991;35:2312-2317. 11. Sanders CC. Cefepime: the next generation? C/in Infect Dis 1993;17:369379. 12. Jacoby GA, Carreras I. Activities of B-lactam antibiotics against Escherichia co/i strains producing extended-spectrum Blactamases. Antimicrob Agents Chemother. 1990;34:858-862. 13. Jones RN, Marshall SA. Antimicrobial activity of cefepime tested against Bush group 1 P-lactamase-producing strains resistant to ceftazidime. Diagn Microbial Infect Dis. 1994;19:33-38. 14. Bush K. Minireviews: characterization of p-lactamases. Antimicrob Agents Chemofher. 1989;33:259-263. 15. Bush K. Classification of plactamases: groups 1, 2a, 211, and 2b’. Antimicrob Agents Chemother. 1989;33:264-270. 16. Bush K. Classification of p-lactamases: groups 2c, 2d, 2e, 3, and 4. Antimicrob Agents Chemother. 1989;33:271-276. 17. Ballow CH, Schentag JJ. Trends in antibiotic utilization and bacterial resistance: report of the National Nosocomial Resistance Surveillance Group. Diagn Microbial Infect Dis. 1992;15fsuppl):37S-42s. 18. Masuyoshi S, Hiraoka M, lnoue M, et al. Comparison of the in vitro and in viva antibacterial activities of cefepime (BMY-28142) with ceftazidime, cefuzonam, cefotaxime and cefmenoxime. Drugs Exp Cfin Res. 1989;15:1-10.

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19. Thornsberry C, Brown SD, Yee YE, et al. In vitro activity of cefepime and other antimicrobials: survey of European isolates. J Antimicrob Chemother. 1993;32fsuppl B):31-53. 20. Washington JA, Jones RN, Gerlach EH, et al. Multicenter comparison of in vitro activities of FK-037, cefepime, ceftriaxone, ceftazidime, and cefuroxime. Anhmicrob Agents Chemother. 1993;37:1696-1700. 21. Dyke JW, Angones D, Bhakta D, Tenjarla G, Kumar A. Antimrcrobial activity of new antibiotics against bacterial isolates from a community hospital. Che motherapy. 1993;39:315-321. 22. Liu YC, Huang WK, Cheng DL. Antibacterial activity of cefepime in vitro. Chemotherapy. 1994;40:384-390. 23. Chow JW, Fine MJ, Shlaes DM, et al. Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy. Ann Intern Med. 1991;115:585-590. 24. Schaberg DR, Culver DH, Gaynes RP. Major trends in the microbial etiology of nosocomial infection. Am J Med. 1991;91(suppl 3B):72S-75s.

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AND YEE 25. Yee YC, Thornsberry C, Brown SD, Bouchillon SK, Marler JK, Rich T. A comparative study of the in-vitro activity of cefepime and other antimicrobial agents against penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae. J Antimicrob Chemother. 1993;:32tsuppl B):1319. 26. National Committee for Clinical Laboratory Standards. Method for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 2nd ed. Approved Standard. NCCLS document M7-A2. NCCLS, Villanova, PA, 1990. 27. Baker CN, Stocker SA, Culver DH, et al. Comparison of the Etesmo agar dilution, broth microdilution, and agar diffusion susceptibility testing techniques by using a special challenge set of bacteria. J Clin Microbial. 1991;29:533538. 28. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests. NCCLS document M2-A4, 4th ed. lO(7). Villanova, PA, 1991.

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