DIAGN MICROBIOLINFECTDIS 1992;15:537-543

537

Cefdinir (FK482), an Orally Administered Cephalosporin in vitro Activity Comparison Against Recent Clinical Isolates from Five Medical Centers and Determination of MIC Quality Control Guidelines E. Hugh Gerlach, Ronald N. Jones, Stephen D. Allen, Franklin P. Koontz, Patrick R. Murray, Michael A. Pfaller, John A. Washington, and Meridith E. Erwin

Cefdinir, a new oral cephalosporin, was compared to cefaclor, cefadroxil, cefixime, and cefuroxime against >5000 recent aerobic clinical isolates. This multicenter study revealed broad-spectrum cefdinir activity against all Enterobacteriaceae (MICsos, O.06-2 i~g/ml) except Enterobacter cloacae, Morganella morganii, Proteus vulgaris, and Serratia marcescens (MICsos, >!4 p~g/ml). Oxacillin-susceptible staphylococci (MICgos, 0.5-2 I~g/ml), E-hemolytic Streptococcus group B (MICgo, 0.06 I~g/ml), and Acinetobacter lwoffii were also susceptible to cef-

dinir. The activity of cefdinir was similar to that of cefixime and cefuroxime against Gram-negative organisms and superior to all tested oral cephems when tested against Gram-positive cocci. None of the cephalosporins were active against oxacillin-resistant Staphylococcus spp., enterococci, Pseudomonas spp., or Xanthomonas maltophilia. MIC quality control range guidelines were established for the strains recommended by the National Committee for Clinical Laboratory Standards documents.

Cefdinir, formerly FK482, PD134393, or CI-983, is an orally administered semisynthetic aminothiazolyloximino-cephalosporin structurally similar to parenteral "third-generation" cephems such as cefotaxime and the C-3 vinyl cefixime (Figure 1) (Inamoto

et al., 1988). Bioavailability of cefdinir seems most comparable to that of cefixime (Shimada and Soejima, 1987; Sakamoto et al., 1988; data on file with Parke-Davis). Phase I h u m a n pharmacokinetic data using volunteers listed a cefdinir Cma× ranging from 0.7 to 1.3 ~g/ml a n d 1.8 to 2.3 ~g/ml for the 200and 400-mg doses, respectively. Jones et al. (1992) suggested that for 300-rag b.i.d, dosing (selected for clinical trials), a susceptible breakpoint of ~1 ~g/ml would be most appropriate and a " ~ 0 . 5 ~g/ml breakpoint would be considered as very conservative." Cefdinir has d o c u m e n t e d in vitro activity against Gram-negative organisms with the exception of Pseudomonas spp. a n d other rarely isolated nonenteric bacilli (Inamoto et al., 1988; Mine et al., 1988; N e u et al., 1989; Briggs et al., 1991). However, cefdinir maintains a balance of activity against m a n y Gram-positive species such as oxacillin-susceptible Staphylococcus spp. and streptococci (Mine et al., 1988; N e u et al., 1989; Briggs et al., 1991).

From the St. Francis Regional Medical Center (E.H.G.), Wichita, Kansas; University of Iowa Hospitals and Clinics (R.N.J., F.P.K., M.A.P., M.E.E.) and the Department of Veterans Affairs Medical Center (R.N.J., M.A.P.), Iowa City, Iowa; Indiana University Medical Center (S.D.A.), Indianapolis, Indiana; Washington University School of Medicine (P.R.M.), St. Louis, Missouri; and the Cleveland Clinic Foundation (J.A.W.), Cleveland, Ohio, USA. Address reprint requests to Dr. E.H. Gerlach, Clinical Microbiology Laboratories, St. Francis Regional Medical Center, Wichita, KS 67214, USA. Received 5 September 1991; revised and accepted 10 October 1991. © 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/92/$5.00

E.H. Gerlach et al.

538

N ~

N~OR II ~.S-.. C--CONH----r---r"

Cefdinir

R = H

Cefixime

R = CH2CEX~

COOH

FIGURE 1 Structural characteristics of cefdinir and cefixime. In this brief report, we present the results of an in vitro study of cefdinir compared with cefaclor, cefuroxime, cefixime and cefadroxil by using freshly isolated aerobic strains. The sample was obtained from five geographically separate medical centers that use reference broth microdilution procedures as described by the National Committee for Clinical Laboratory Standards (NCCLS, 1990). Quality control (QC) limits for broth microdilution tests were also determined (NCCLS, 1989 and 1990). The cefdinir was supplied by Parke-Davis (Ann Arbor, MI), and the comparison compounds were provided by the following manufacturers: cefixime by Lederle Laboratories (Pearl River, NY), cefuroxime by Glaxo (Research Triangle Park, NC), cefaclor by Eli Lilly (Indianapolis, IN), and cefadroxil by Bristol-Myers Squibb (Wallingford, CT). The five medical centers participating in the study were the University of Iowa Hospitals and Clinics, Iowa City, IA (coordinating center); St. Francis Regional Medical Center, Wichita, KS; Indiana University Medical Center, Indianapolis, IN; Barnes Hospital and Washington University Medical Center, St. Louis, MO; and the Cleveland Clinic Foundation, Cleveland, OH. Each of the participating medical centers tested a

TABLE 1

minimum of 1000 recent clinical isolates of aerobic bacteria. The number of each bacterial species tested are listed in Tables 2 and 3. All of the strains were tested using the broth microdilution method as described by the NCCLS (1990). The test medium was cation-adjusted Mueller-Hinton broth. The test trays were prepared by each laboratory. There was an identical set of trays prepared by the coordinating laboratory (R.N.J.). These latter trays were referred to as the common lot, and those produced by each laboratory were referred to as unique lots of trays. The QC strains (Staphylococcus aureus ATCC 29213, Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, and Pseudomonas aeruginosa ATCC 27853) were tested on five occasions with the common lot and a minimum of 20 times with the unique lot of trays produced at each center. These results generated sufficient data to establish minimum inhibitory concentration (MIC) QC ranges (Table 1) for cefdinir by NCCLS (1989) guidelines. Table 1 summarizes the QC trial results using six unique lots (20 replicates each) and a Mueller-Hinton broth lot common to each study participant. The following MIC ranges were proposed for cefdinir tests: E. coli ATCC 25922 = 0.12-0.5 ~g/ml, Ent. faecalis ATCC 29212 = 1-4 ~g/ml, P. aeruginosa ATCC 27853 = >4 ~g/ml, and S. aureus ATCC 29213 = 0.12-0.5 ~g/ml. A total of 89.2%-100% of study MIC results were found within these recommended limits, including 98.2% of all common-lot cefdinir MICs. The MIC results of 3416 Gram-negative organisms are found in Table 2. Pseudomonas spp., P. aeruginosa, Xanthomonas maltophilia, and Acinetobacter spp. were resistant to all tested drugs, although cefdinir inhibited the greatest percentage (23%-58%) of acinetobacters, depending upon the applied breakpoint concentration. The Enterobacteriaceae were generally most susceptible to cefixime followed in activity by cefdinir and cefuroxime. The most cefdi-

Cefdinir MIC Quality Control Guidelines Determined by M23-T Conforming Studies at Five Participating Medical Centers a

Organism

Escherichia coli ATCC 25922

No. of Occurrences at MIC (~g/ml) Medium Lots 0.06 0.12 0.25 0.5 1 2 4 >4

Unique Common Enterococcus faecalis ATCC 29212 Unique Common Pseudornonas aeruginosa A T C C Unique 27853 Common Staphylococcus aureus ATCC 29213 Unique Common

0 0 0 0 0 0 1 2

[11 1 0 0 0 0 [30 3

93 19 0 0 0 0 58 17

16]b 0 0 0 0 10 0 0 0 0 0 [45 44 18] 13 0 10 19 1 0 0 0 0 0 [120] 0 0 0 0 30 31] 0 0 0 0 8 0 0 0 0

aM23-T(NCCLS, 1989);equal or more than fivemediumlots as recommendedby NCCLS(1989). bBrackets indicate proposed dilution range determined by commonand unique lot data.

Note

539

nir-susceptible enteric bacilli w e r e E. coli (MICgo, 0.5 ~g/ml), Klebsiella s p p . (MIC90s, 0.25-2 ~g/ml), a n d Proteus mirabilis (MIC90, 0.12 ~g/ml). The least cefdinir-susceptible species w e r e Ent. cloacae (23% of

TABLE 2

MICs at --16 >16 >16

>4 >16 >16 >16

0.25->4 2->16 0.25->16 2->16

>2

>2

2->2

0.5

>4

0.12->4

8 1 4

>16 8 >16

2->16 0.5->16 1->16

70 90 50

40

23 (58) 5 8 5 0

Cefdinir Cefadroxil Cefaclor Cefuroxame Cefixime

>2

>2

0.5->2

Pseudomonas aeruginosa (600)

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

>4 >16 >16 >16 >2

>4 >16 >16 >16 >2

0.25->4 4->16 4-->16 4-->16 0.25->2

Pseudomonas spp. (18)b

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

>4 >16 >16 8 >2

>4 >16 >16 >16 >2

~4 1->16 0.25->16 0.5->16 ~0.015->2

Xanthomonas maltophilia (76)

Cefdinir Cefadroxil Cefaclor Cefuroxlme Cefixime

>4 >16 >16 >16 >2

>4 >16 >16 >16 >2

4->4 >16 16->16 8->16 2->2

Other non-Enterobacteriaceae spp. (13)c

Cefdinir Cefadroxil Cefaclor Cefuroxame Cefixime

>4 >16 >16 8 >2

>4 >16 >16 >16 >2

~4 0.25->16 0.25->16 ~16 ~2

38 (46) 23 23 46 38

Citrobacter diversus (46)

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

4 >16 >16 >16 2

~0.03->4 1->16 0.5->16 0.5->16 0.03-2

87 (89) 72 76 70 89

C. freundii (98)

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

2 >16 >16 2

>4 >16 >16 >16 >2

~4 2->16 0.5->16 1->16 ~2

46 (52) 10 9 60 37

Cefdinir Cefadroxil

2 >16

>4 >16

0.06->4 1->16

A. lwoffii (10)

Enterobacter aerogenes (161)

0.12 8 1 4 0.06

4

80 (80)

0 (0) 1 1 0 0 17 (44) 39 33 44 28 0 (0) 0 0 1

0

46 8

(53)

E . H . G e r l a c h et al,

540

TABLE 2

Continued MIC (p.g/ml)

Organism (No. Tested)

Cephalosporin Cefaclor Cefuroxime Cefixime

50% >16 8 1

90%

Range

% Susceptible a

>16 >16 >2

0.25->16 ~16 0.03->2

6 48 54

>4 >16 >16 8 2

~4 2->16 0.25->16 0.25->16 ~4 >16 >16 >16 >2

0.06->4 1->16 2->16 0.5->16 0.03->2

23 8 3 25 48

(28)

>4 >16 >16 >16 >2

0.06->4 4->16 0.5->16 2->16 0.03->2

64 36 43 64 57

(64)

E. agglomerans (18)

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

E. cloacae (322)

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

Enterobacter spp. (14) d

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

1 16 16 8 0.25

Escherichia coli (1029)

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

0.12 8 2 2 0.25

0.5 16 8 8 0.5

4 1->16 ~16 ~16 ~2

97 78 92 90 96

(98)

Klebsiella oxytoca (95)

Cefdimr Cefadroxil Cefaclor Cefuroxime Cefixime

0.12 8 1 2 0.03

2 8 4 8 0.12

~4 2->16 0.25->16 ~16 ~2

89 93 92 81 96

(94)

K. pneumoniae (391)

Cefdinir Cefadroxil Cefaclor Cefuroxame Cefixlme

0.12 8 1 2 0.03

0.25 16 4 8 0.12

~4 2->16 0.25->16 ~16 ~2

98 82 98 86 98

(99)

Morganella morganii (69)

Cefdimr Cefadroxil Cefaclor Cefuroxame Cefixime

>4 >16 >16 >16 1

>4 >16 >16 >16 >2

~4 8->16 4->16 ~16 ~2

7 12 1 14 52

(17)

Proteus mirabilis (194)

Cefdinir Cefadroxil Cefaclor Cefuroxlme Cefixime

0.06 16 1 0.5 ~16 2 2 ~16 >16 >16 40.015

>4 >16 >16 >16 0.03

4 4->16 0.25->16 0.5->16 ~16

>4 >16

~4 16->16

77 0

(77)

0.06 4 1 0.5 0.03 >4 >16 >16 16 >2

Note

541

TABLE 2

Continued MIC (~g/ml) % Susceptible a

50%

90%

Range

Cefaclor Cefuroxime Cefixime

>16 2 ~0.015

>16 16 0.5

4->16 ~0.12-> 16 ~0.015->2

Serratia marcescens (105)

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

>4 >16 > 16 >16 0.5

>4 >16 > 16 >16 >2

0.5->4 8->16 0.5-> 16 2->16 0.03->2

1 (8) 3 1 4 72

Serratia spp. (10)e

Cefdinir Cefadroxil Cefador Cefuroxime Cefixime

1 > 16 >16 >16 0.25

>4 > 16 > 16 >16 2

0.25->4 > 16 8 - > 16 2->16 0.06->2

60 (60) 0 10 10 70

Other Enterobacteriaceae (36)~

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

0.5 8 4 4 O.12

>4 > 16 > 16 > 16 2

~4 4 - > 16 0.5-> 16 ~0.12-> 16 ~0.015->3

64 (69) 56 64 53 89

Organism (No. Tested)

Cephalosporin

8 69 92

aSusceptibility criteria per NCCLS M7-A2 (1990). Cefdinir susceptibility is defined as ~1 p,g/ml and the higher breakpoint of 42 ~g/ml is in parenthesis. bIncludes P. stutzeri (6 strains), Pseudomonas spp. (5 strains), P. fluorescens (3 strains), P. putida (3 strains), and P. picketti (1 strain). qncludes Aeromonas hydrophila (4 strains), Achromobacter xylosoxidans (3 strains), and one strain each of Agrobacterium radiobacter, Alcaligenes spp., Bordetella bronchoseptica, CDC group VA, Pasteurella haaemolyticus, and Pasteurella multocida. qncludes E. sakazakii (4 strains), E. taylorae (4 strains), E. amnigenus (2 strains), E. geogoviae (2 strains), and E. vulneris (2 strains). qncludes S. liquefaciens (6 strains), S. odorifera (2 strains), and S. rubidaea (2 strains). flncludes the following 10 species: C. amalonaticus (6 strains), Providencia stuartii (6 strains), Salmonella enteritidis (6 strains), Escherichia hermannii (4 strains), Kluyvera spp. (4 strains), and two strains each of Hafnia alvei, Proteus penneri, Shigella sonnei, and Yersinia enterocolitica.

Table 3 contains the MIC results from tests with 1785 G r a m - p o s i t i v e bacteria. Cefdinir w a s clearly m o r e p o t e n t t h a n a n y c o m p a r i s o n oral c e p h a l o s p o r i n . The cefdinir MICs0 for S. aureus, Staphylococcus epidermidis, a n d o t h e r c o a g u l a s e - n e g a t i v e staphylococci w a s 0.12-0.25 ~g/ml, four- to eightfold greater activity than the next best c o m p o u n d , cefuroxime. The MIC90 results w e r e a d v e r s e l y influenced b y a > 10% incidence of oxacillin-resistant isolates (data not shown). W h e n

TABLE 3

these oxacillin-resistant staphylococcal strains w e r e deleted f r o m the analyses, the cefdinir MIC9os w e r e 0.5 ~g/ml for S. aureus a n d 0.5 lag/ml for all cited coagulase-negative staphylococci (Table 3). Cefixime was active against -4 ~g/ml).

In vitro Activity of Cefdinir (FK482) C o m p a r e d w i t h T h r e e O t h e r Orally A d m i n i s t e r e d C e p h a l o s p o r i n s Tested A g a i n s t 1700 G r a m - P o s i t i v e O r g a n i s m s Isolated f r o m Five Medical Centers MIC (~g/ml)

Organism (No. Tested) Staphylococcus aureus (794)

Cephalosporin Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

50% 0.25

90% 4

(0.5) b

Range ~0.03->4

2

>16

0.5->16

4 1 >2

>16 4 >2

0.25->16 ~0.12-> 16 0.5->2

Susceptible ~ 88 87 83 91 3

(90)

E . H . G e r l a c h et al,

542

TABLE 3

Continued MIC Ozg/ml)

Organism (No, Tested)

Cephalosporin

50%

90%

Range

Susceptible a

S. epidermidis (87)

Cefdinir Cefadroxi| Cefaclor Cefuroxime Cefixime

0.25 16 8 2 >2

>4 (0.5) b >16 >16 >16 >2

0.03->4 0.5->16 0.25->16 40.12->16 1->2

62 49 59 70 1

(67)

S. haemolyticus (12)

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

0.25 8 4 2 >2

>4 (0.5) b >16 >16 >16 >2

40.03->4 2->16 1->16

67 50 58

(67)

0.5->16

58

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

0.12 2

1 8

1 1

8 4

>2

>2

Staphylococcus spp. (24) c

Coagulase-negative, Staphylococcus spp. (419)

(0.5) b

>2 0.06->4 40.12->16

0 (96)

0.5->2

96 96 92 96 4

40.03->4 0.12->16 40.12->16 ~ 16 0.25->2

71 63 66 79 8

(74)

~16 ~16

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

>2

>2

Streptococcus, gr. B (52)

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

40.03 1 1 40.12 0.25

0.06 1 1 ~16 >16 >16 >2

>4 >16 >16 >16 >2

0.25->4 8->16 8->16 1->16 1->2

4 1 2 3 0

(17)

Enterococcus spp., N O S (140)

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

>4 >16 >16 >16 >2

>4 >16 >16 >16 >2

0.5->4 ~16 ~ 16 1->16 1->2

4 4 6 1 1

(16)

Other Gram-positive organisms (12)d

Cefdinir Cefadroxil Cefaclor Cefuroxime Cefixime

1 1 0.5 8 >2

>4 >16 >16 >16 >2

40.03->4 0.25->16 0.25->16 40.12->16 0.06->2

50 67 58 42 25

(50)

0.12 8 4

>4 (0.5) b >16 >16

1

> 16

40.03-0.06 0.254 0.25-4 40.12-1 40.015-2

100 (100) 100 10(9 100 98

aSee note a, Table 2. bMIC9o of oxacillin-susceptible strains only. qncludes S. hominis (6 strains), S. saprophyticus (6 strains), S. warneri (6 strains), S. simulans (5 strains), and one strain of S. capiti~ aEnterococcus spp. not otherwise speciated.

Note

Numerous oral cephalosporins are currently under investigation that have structural modifications generally improving Gram-negative antimicrobial activity and/or clinical pharmacokinetics (Neu, 1986; Jones, 1988). The introduction of a C-3 vinyl group to C-7 aminothiazolyl cephems improved oral bioavailability, but the spectrum was limited to most enteric bacilli and fastidious respiratory tract pathogens (Neu et al., 1984; Jones 1988). Further introduction of a hydroxyirnino group for the carboxymethoxyimino substitution on cefixime produced cefdinir, a substance with excellent Gram-positive antimicrobial potency (Inamoto et al., 1988; Mine et

543

al., 1988; Neu et al., 1989; Briggs et al., 1991). However, some decrease of Gram-negative activity was observed for cefdinir compared to cefixime. Using two possible susceptible breakpoint concentrations for cefdinir of ~1 or ~2 ~g/ml (Sakamoto et al., 1988; Shimada and Soejima, 1987), cefdinir had a very well balanced spectrum against aerobic pathogens that frequently cause respiratory, urinary, cutaneous, and genital infections in outpatients. In vitro cefdinir susceptibility testing with standardized MIC methods was easily performed and will be enhanced by the determination of QC parameters for the clinical trials.

REFERENCES Briggs BM, Jones RN, Erwin ME, Barrett MS, Johnson DM (1991). In vitro activity evaluations of cefdinir (FK482, CI-983, PD1343930): a novel orally administered cephalosporin. Diagn Microbiol Infect Dis 14:425-434. Inamoto Y, Chiba T, Kamimura T, Takaya T (1988) FK482, a new orally active cephalosporin: synthesis and biological properties. J Antibiot 41:828-830. Jones RN (1988) Antimicrobial activity, spectrum and pharmacokinetics of old and new orally administered cephems. Antimicrob Newsl 5:1-7. Jones RN, Erwin ME, Gooding BB (1992) Interpretive criteria for cefdinir 5-~g disk diffusion tests with rapidly growing clinical isolates. J Clin Microbiol 30:1022-1023, 1992. Mine Y, Kamimura T, Watanabe Y, Tawara S, Matsumoto Y, Shibayama F, Kikuchi H, Takaya T (1988) In vitro antibacterial activity of FK482, a new orally active cephalosporin. J Antibiot 41:1873-1889. National Committee for Clinical Laboratory Standards (NCCLS) (1989) Tentative standard M23-T: development of in vitro susceptibility testing criteria and quality control parameters. Villanova, PA: NCCLS.

National Committee for Clinical Laboratory Standards (NCCLS) (1990) Approved standard M7-A2: standard methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Villanova, PA: NCCLS. Neu HC (1986) Beta-lactam antibiotics: structural relationships affecting in vitro activity and pharmacologic properties. Rev Infect Dis 8(Suppl 3):237-259. Neu HC, Chin NX, Labthavikul P (1984) Comparative in vitro activity and 13-1actamase stability of FR 17027, a new orally active cephalosporin. Antimicrob Agents Chemother 26:174-180. Neu HC, Saha G, Chin NX (1989) Comparative in vitro activity and f~-lactamase stability of FK482, a new oral cephalosporin. Antimicrob Agents Chemother 33:1795-1800. Sakamoto H, Hirose T, Nakamoto S, Hatano K, Shibayama F, Kikuchi H, Mine Y (1988) Pharmacokinetics of FK482, a new orally active cephalosporin, in animals. J Antibiot 41:1896-1905. Shimada K, Soejima R (1987) FK482, a new orally active cephalosporin: pharmacokinetics and tolerance in healthy volunteers [abst 655]. In 27th Intersociety Conference for Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology.

Cefdinir (FK482), an orally administered cephalosporin in vitro activity comparison against recent clinical isolates from five medical centers and determination of MIC quality control guidelines.

Cefdinir, a new oral cephalosporin, was compared to cefaclor, cefadroxil, cefixime, and cefuroxime against greater than 5000 recent aerobic clinical i...
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