Original articles
Cefditoren activity against nearly 1000 non-fastidious bacterial isolates and the development of in vitro susceptibility test methods

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Abstract

Cefditoren (formerly ME-1206) is an investigational, orally administered cephalosporin ester with bactericidal activity against many Gram-positive and -negative organisms. Cefditoren potency against nearly 1000 non-fastidious species was determined by National Committee for Clinical Laboratory Standards (NCCLS) reference broth microdilution and standardized disk diffusion methods. Against staphylococci, usable cefditoren activity was completely correlated with oxacillin with respect to potency and susceptibility interpretation (mec A-negative strains). Cefditoren was very active against Klebsiella spp., Proteus mirabilis, Salmonella spp., and Escherichia coli (MIC90 range, 0.12–1 μg/ml; median zone, 23–26 mm). Cefditoren had more limited activity against Citrobacter spp., Enterobacter spp., Serratia marcescens, and indole-positive Proteae (MIC50 range, 0.12–1 μg/ml; MIC90, > 16 μg/ml; median zone, 18–25 mm). Against Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Acinetobacter spp., and other non-fermentors, cefditoren was inactive (MIC90, > 16 μg/ml; zone, 6 mm). Pharmacokinetic analysis of cefditoren showed that utilized dosages produce a plasma concentration that exceeds 0.5 μg/ml for 5 to 8 h and 1 μg/ml for 4 to 6 hours (T1/2 ranges from 1.5–2 h). The following interpretive criteria were suggested: ≤ 2 μg/ml or ≥ 15 mm (susceptible) and ≥ 8 μg/ml or ≤ 11 mm (resistance) that yielded an intermethod categorical agreement of 95.8% and very major or major error rates of 0.7% and 0.3%, respectively. Alternatively, ≤ 1 μg/ml or ≥ 18 mm (susceptible) and ≥ 4 μg/ml or ≤ 14 mm (resistant) breakpoints resulted in 96.2% accuracy and combined serious errors of only 1.1%. Cefditoren was observed to be a very active cephalosporin ranking among the most potent available orally active β-lactams for use against a wide variety of pathogens.

Introduction

Cefditoren, formerly ME-1206, is a methoxyamino cephalosporin utilized clinically as a pivoxil ester that enhances oral absorption. Its documented potency resembles that of so-called “third-generation” cephalosporins and has particularly high activity against the typical bacterial pathogens causing community-acquired respiratory tract infections such as Streptococcus pneumoniae (MIC90, 0.015–2 μg/ml), Haemophilus influenzae (MIC90, 0.015 μg/ml), and Moraxella catarrhalis (MIC90, 0.5 μ/gml) [Jones et al 1998, Soriano et al 1996; Spanger et al., 1996]. This cited activity was superior to that recorded for other orally administered β-lactams such as cefaclor, cefprozil, cefuroxime axetil, cefixime, cefpodoxime, amoxicillin with or without clavulanate, and loracarbef [Jones et al., 1998]. Similar potencies for cefditoren have been reported by several other in vitro investigations against oxacillin-susceptible staphylococci, Enterobacteriaceae, and some fastidious Gram-negative species [Chin et al 1991, Felmingham et al 1994; Tamura et al., 1998]. These antibacterial characteristics most resembled activity listed for other newer cephalosporin esters such as cefpodoxime.

Cefditoren was provided by TAP Holdings Pharmaceuticals, Inc. (Deerfield, IL, USA). The organisms tested were isolated from various types of infections (usually blood stream) at the University of Iowa Hospitals and Clinics (Iowa City, IA, USA) or from other United States medical centers (> 30 sites) participating in various antimicrobial surveillance programs in 1999. A total of 998 strains were tested, each identified by routine methods used at the institution of initial isolation and confirmed by reference techniques at the referral location (University of Iowa College of Medicine, Iowa City, IA, USA). These strains were enterococci (91 strains), Staphylococcus aureus (200 strains), coagulase-negative staphylococci (100 strains), Enterobacteriaceae (480 strains; 12 species), Acinetobacter spp. (29 strains), Pseudomonas aeruginosa (70 strains), Stenotrophomonas maltophilia (20 strains), and other non-fermentative Gram-negative species (eight strains), see Table 1.

Cefditoren was dispensed into broth microdilution trays in a serial two-fold concentration range of 0.008–16 μg/ml (PML Microbiologicals, Wilsonville, OR, USA). All trays were held at −70°C or below until used. The trays were brought to room temperature before inoculation (5 × 105 CFU/ml) and the technical details of the National Committee for Clinical Laboratory Standards (NCCLS) [1997b] documents were followed. The 5-μg cefditoren disks were produced by BD Microbiology Systems (Cockeysville, MD, USA) and these reagents were used following the NCCLS method M2-A5 [NCCLS, 1997a]. The MIC and zone diameter of inhibition were read as defined by the NCCLS [1997a and b]. The results were compared by scattergram, regression statistics, error-rate bounding and breakpoints for susceptibility were proposed based on available cefditoren pharmacodynamic data [TAP Holdings, data on file] and NCCLS [1998] guidelines. Quality control was performed with Esherichia coli ATCC 25922, S. aureus ATCC 25923 and 29213, and Enterococcus faecalis ATCC 29212; all results were within limits approved by the NCCLS in June 1999 [NCCLS Subcommittee on Antimicrobial Testing Minutes, June 13–15, 1999].

Table 1 summarizes the cefditoren MIC and zone diameter results for 998 strains of rapid growing bacterial species. Several species/genus groups of Enterobacteriaceae were very susceptible to cefditoren (MIC90, ≤ 1 μg/ml). These organisms included E. coli, Klebsiella spp., Proteus mirabilis, and Salmonella spp. Although Citrobacter spp., Enterobacter spp., Morganella morganii, Providencia spp., and S. marcescens MIC50 results for cefditoren were ≤ 1 μg/ml, at least 10% of each species/genus group had elevated values (MIC90, > 16 μg/ml). These results most resembled cefpodoxime and cefixime, agents used as comparison drugs (data not shown). In contrast, few strains of non-fermentative Gram-negative bacilli were inhibited by cefditoren (MIC50, > 16 μg/ml; mean zone diameter, 6 mm). Enterococci were not inhibited by cefditoren (MIC50, > 16 μg/ml; mean zone diameter, 6 mm). Cefditoren was very active and equally potent by weight to oxacillin against oxacillin-susceptible staphylococci (mec A-negative strains) inhibiting 99% of S. aureus at 2 μg/ml and 100% of coagulase-negative staphylococci at 0.25 μg/ml (data not shown).

When the cefditoren MICs and zones were compared, the regression equation was y = 15.7 − 0.35× with an excellent correlation coefficient (r) of 0.93. Pharmacokinetic results for a 400 mg dose result in a Cmax of 4.6 μg/ml and produces a T1/2 of 1.5 to 2 h [TAP Holdings Inc, data on file]. These parameters would be sufficient to support ≤ 1 and possibly ≤ 2 μg/ml susceptible breakpoints for twice daily dosing schedules. The ≤ 2 μg/ml susceptible breakpoint (correlate zone diameter, ≥ 15 mm) indicates a very acceptable level of intermethod error. The very major (false-susceptible) error rate was only 0.7%, major (false-resistant) error was 0.3% and the minor error was 3.2%; total absolute agreement between tests was 95.8%. The seven very major errors for the ≤ 2 μg/ml breakpoint were contributed by six species (Citrobacter freundii, C. koseri, Morganella morganii, P. aeruginosa, Providencia stuartii, and S. aureus). The two errors for the S. aureus strains were among oxacillin-resistant strains that would have been categorized as resistant from the oxacillin test results e.g. no error and a corrected (adjusted) reduction of very major error rates to only 0.5%. If the breakpoint was lowered to ≤ 1 μg/ml (correlate zone diameter, ≥ 18 mm; Fig. 1), the serious errors were 1.1% and the minor error was only 2.7%; total absolute agreement was again very high at 96.2%.

In similar experiments for Streptococcus pneumoniae, Kelly et al. [1999] recommended a breakpoint of ≥ 16 mm for the ≤ 2 μg/ml cefditoren breakpoint. No error was observed because cefditoren was active against all strains at the proposed MIC breakpoint. Ideally, the same interpretive criteria for cefditoren susceptibility should be applied to all indicated infections and pathogens. These preliminary results indicate that possibility might be achieved and further studies using Haemophilus spp. and other fastidious streptococci [Johnson et al., in press] validates the studies of Kelly et al. [1999]. Other methods such as the Etest (AB BIODISK, Solna, Sweden) have also been applied using cefditoren strips with excellent test accuracy. Our results confirm those of previous studies, demonstrating cefditoren to be one of the most potent orally delivered β-lactams and this agent certainly warrants further clinical investigations. National Committee for Clinical Laboratory Standards 1999, Spangler et al 1996, Tamura et al 1988.

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Acknowledgements

The co-authors wish to acknowledge the excellent support of the research and manuscript preparation contributed by: M.D. Mayer, D.J. Mulford, K.L. Meyer, M.E. Erwin, and M.L. Beach.

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