DIAGN MICROBIOL INFECT DIS 1992;15:633-640

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In vitro Activity of Cefprozil (BMY 28100) and Cefepime (BMY 28142) Against Streptococcus pneumoniae, Branhamella catarrhalis, and Haemophilus influenzae, and Provisional Interpretive Criteria for Disk Diffusion and Dilution Susceptibility Tests with Haemophilus

influenzae Gary V. Doern and Raymond Vautour

The in vitro activities of two new cephalosporins, an oral agent, cefprozil and a parenteral compound, cefepime, were assessed against recent clinical isolates of Streptococcus pneumoniae, Moraxella (Branhamella) catarrhalis, and Haernophilus influenzae. In general, both cefprozil and cefepime MICs were higher for ~8-lactamase-producing strains of M. catarrhalis in comparison to strains that lacked ~8-lactamase. By contrast, ~-lactamase-positive and -negative strains of H. influenzae had similar cefprozil and cefepime minimum inhibitory concentrations (MICs). The MIC9o values for cefprozil were 0.12, 32, 4.0, and 0.5 I~g/ml versus S. pneumoniae, H. influenzae, and jS-lactamase-positive and negative strains of M. catarrhalis, respectively. In comparison to three other oral cephalosporins included in this study, cefaclor, cefuroxime axetil, and cefixime, cefprozil was the most active agent against S. pneumoniae, the least active against B. catarrhalis, and equivalent in activity to cefaclor against H. influenzae. The cefepime MIC values against S. pneurnoniae, H. influenzae, and AS-lactamase-positive and negative strains of M. catarrhalis were 0.03, 0.25, 2.0, and 0.5 I~g/ml, respec-

From the Department of Clinical Microbiology, University of Massachusetts Medical Center, Worcester, Massachusetts, USA. Address reprint requests to Dr. G. V. Doern, Department of Clinical Microbiology, University of Massachusetts Medical Center, 55 Lake Avenue, North, Worcester, MA 01655, USA. Received 5 September 1991; revised and accepted 3 January 1992. © 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/92/$5.00

tively. Cefepime was less active than ceftriaxone for all three organism groups, however, was in all cases more active than cefi'xime, cefuroxime, cefaclor, and cefprozil. The following susceptibility test interpretive criteria are proposed for use when testing H. influenzae against cefprozil and cefepime using Haemophilus test medium (HTM): cefprozih 315 mm ( cefprozil; a n d H. influenzae, cefixime > cefuroxime > cefaclor = cefprozil. Cefprozil w a s the m o s t active of these four oral agents against S. pneumoniae but w a s t o g e t h e r w i t h cefaclor, the least active against M. catarrhalis a n d H. influenzae. Of the 250 test strains of H. influenzae, 40 (16%) w e r e , h o w e v e r , f o u n d to be resistant to cefprozil. T h e s e included s e v e n of the 10 ampicillin resistant, ~-lactamase-negative strains of H. influenzae. T h e s e o b s e r v a t i o n s are generally consistent w i t h the results of p r e v i o u s investigations that e x a m i n e d smaller n u m b e r s of org a n i s m s (Aldrich et al., 1987; Chin a n d N e u , 1987; Hiraoka et al., 1987; Kayser, 1987; Leitner et al., 1987). Cefepime, a new parenteral cephalosporin, was more active than cefaclor and cefuroxime a n d slightly less active t h a n ceftriazone for all three of the org a n i s m g r o u p s e x a m i n e d in this study. In c o m p a r -

ison to cefixime, an orally a d m i n i s t e r e d e x t e n d e d s p e c t r u m c e p h a l o s p o r i n , c e f e p i m e w a s m o r e active against S. pneumoniae, b u t less active against M. catarrhalis a n d H. influenzae. The h i g h e s t c e f e p i m e MIC obtained with a n y s t u d y strain w a s 4.0 ~g/ml. These results are similar to the o b s e r v a t i o n s of others w h o have e x a m i n e d smaller n u m b e r s of strains (Bodey et al., 1985; Fuchs et al., 1985; Kessler et al., 1985). The ~-lactamase of H, influenzae did not s e e m to influence the activity of cefprozil or cefepime. These results are consistent w i t h the p r e v i o u s o b s e r v a t i o n s that T E M - l - t y p e ~-lactamases such as that p r o d u c e d b y H. influenzae do not effectively h y d r o l y z e cefprozil (Hiraoka et al., 1987). By contrast, the cefprozil a n d cefepime MICs o b t a i n e d w i t h ~-lactamase-positive strains of M. catarrhalis tended to be m u c h higher t h a n those o b t a i n e d w i t h strains that lacked f~-lactamase. The s a m e p a t t e r n w a s o b s e r v e d with o t h e r

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G.V. Doern and R. Vautour

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FIGURE 1 Comparisons of zones of inhibition and minimum inhibitory concentrations for 250 strains of Haemophilus influenzae tested by using Haemophilus test medium against cefprozil (a) and cefepime (b).

cephalosporins in the current study and in other studies that have examined larger numbers of strains of [3-1actamase-negative M. catarrhalis (Doern and Tubert, 1988; Jorgensen et al., 1990a; Wallace et al., 1990). Based on the results of this study, it is unclear what clinical advantage can be expected of cefprozil

in comparison to three currently licensed, orally administered cephalosporins, cefaclor, cefuroxime axetil, and cefixime in the management of infections due to H. influenzae and B. catarrhalis. Cefprozil may, however, be of utility in the management of certain infections due to all three of these organisms. In view of the potential clinical use of cefprozil

In vitro Activity of Cefprozil and Cefepime

and cefepime, an attempt was made to develop tentative interpretive criteria for disk diffusion and MIC tests with these agents. This portion of the study was restricted to H. influenzae, since this is the only organism among the three included in this study for which an accepted standardized disk diffusion susceptibility test medium and method have been described (Doern et al., 1990 and 1991a; Jorgensen et al., 1987; NCCLS, 1990a and b). Previous studies (Fuchs et al., 1986; Jones and Barry, 1987) have described disk diffusion and dilution susceptibility test interpretive criteria for cefprozil and cefepime against nonfastidious bacteria tested using unsupplemented Mueller-Hinton medium. These criteria--that is, ---18 mm (~8.0 ~g/ml) = susceptible, 15-17 mm (16 ~g/ml) = moderately susceptible, and ~14 m m (~32 ~g/ml) = resistant-appear to have been chosen largely by analogy with the criteria previously applied to most other cephalosporins (NCCLS, 1990a and b). Based on the results of the current study, these same criteria also appear to apply to H. influenzae when tested on HTM agar with a 30-p~g cefprozil disk. Different criteria, however, were chosen for cefepime.

639

With cefepime, no dearly resistant organisms were available for testing in this study. As a result, in a manner analogous to what the NCCLS has done with other extended-spectrum cephalosporins versus H. influenzae, only a susceptible category was defined (NCCLS, 1990a and b). A zone diameter of ->26 mm was chosen with an MIC correlate of -