New Antimicrobial Agents

Vol. 11. No. 2

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Antibacterial Activity of the lnvestigationai Oral and Parenteral Cephalosporin BK-218 D.M. Johnson, R.N. Jones*

BK-218 is a novel cephalosporin with a dual route of administration and spectrum of activity most similar to that of second-generation cephaloSporins. BK-218 was active against Streptococcus Pneumoniae, Haemophilus influenzae and Moraxella catarrhalis but strains resistant to Penicillins had higher MICs. BK-218 had greater activity (8-fold) than cefuroxime or cefacior against oxacillin-susceptible Staphylococcus spp. Moderate BK-218 activity was observed against Neisseria gonorrhoeae and commonly isolated Enterobacteriaceae such as Escherichia coli (MIC90, I mg/I), Klebsiella spp. (MIC90, 2 mg/I), and Proteus mirabilis (MIC90, 2 rag/I). The following organisms were generally BK-218-resisrant (MIC90, > 16 mg/I): Bacteroides fragilis, Pseudomonas spp., Acinetobacter spp., Xanthomonas maltophllia, C3trobacter spp., Enterobacter spp., indole-positive Proteus, Serratia spp., enterococci and oxacillin-resistant staphylococci.

BK-218 is a new orally and parenterally administered cephalosporin (1). BK-218 has a chlorine attached to the 7-position side chain. The presence of a chlorine at the3' position of cefaclor (the only available chlorinated cephalosporin) increases oral bioavailability and antimicrobial activity (2). The BK-218 3' position substitution, a N-methyl thiotetrazole (Figure 1) is identical to that found on parenteral cephems such as Cefamandole, cefmetazole, cefotetan and cefoperazone. In a previous study (1), BK-218 was found to be active again s t m any st ra in s o f En terobacteriaceae, Staphylococci, Streptococcus spp., fastidious respiratory tract pathogens (Moraxella catarrlzalis, Haemophilus influenzae) and some anaerobes. Only a limited number of organisms Anti-infectives Research Center, Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.

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181

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Figure 1: Chemical structure of BK-218. tested were taken from a stock culture collection. BK-218 was also moderately stable to the hydrolysis of several clinical prevalent beta-lac. tamases investigated (1). Like BK-218, several other investigational orally administered cephalosporins have been described that provide increased potency against gram-negative pathogens and a greater beta-lactamase stability (3). Two of these compounds are cefixime (4) and cefuroxime axetil (3, 5). Many of these newer cephalosporins have limited bioavailability (3, 6). In this study BK.218 activity was compared to cefuroxime (5), cefixime (4), cefaclor (2) and the widely used fluoroquinotone, ciprofloxacin, against over 600 recent clinical isolates. In addition, beta-lactamase stability was assessed by comparing BK-218, cefixime, cefaclor, and cefotaxime MICs tested against beta-lactamase producing type strains.

Materials and Methods. BK-218 was provided by Biogal Pharmaceutical Works (Debrecen, Hungary). Cefixime was obtained from Lederle Laboratories (Pearl River, NY, USA), cefuroxime from Glaxo Inc. (Research Triangle Park, NC, USA), cefaclor from Eli Lilly (Indianapolis, IN, USA) and ciprofloxacin from Miles Laboratories (West Haven, CT, USA). The organisms tested against BK-218 and structurally related cephalosporins were recent clinical isolates from patients at the University of Iowa Hospitals and Clinics (Iowa City, Iowa). The strains were distributed as follows: 208 Enterobacteriaceae, 10 Acinetobacter anitratus, 31 Haemophilus influenzae (11 beta-lactamase positive, 10 beta-lactamase negative ampicillin-susceptible, and 10 beta-lactamase negative ampicillin resistant), 20 Moraxella catarrhalis (10 betalactamase positive, 10 beta-lactamase negative), 34 Neisseria gonorrhoeae, 16 Neisseria spp., 28 Pseudomonas aeruginosa, 10 Xanthomonas raaltophilia, 20 Bacteroidesfragilis, 41 enterococci, 91 staphylococci (11 oxacillin-resistant Staphylococcus aureus), 30 Streptococcus spp. and 6 Bacillus cereus. Also, 28 strains from 13 species were

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Eur. J. Clin. Microbiol. Infect. Dis.

T a b l e 1 : B K - 2 1 8 a n t i m i c r o b i a l activity c o m p a r e d to o t h e r orally a d m i n i s t e r e d d r u g s t e s t e d a g a i n s t 414 g r a m - n e g a t i v e bacteria.

M I C (mg/l)

Organism (n)

Antimicrobial agent

Citrobacter diversus (10)

BK-218 Cefixime Cefuroxime Cefaclor Ciprofloxacin

2 0.06 4 0.5 < 0.008

> 16 0.12 32 1 0.015

0.25 0.03 2 0.5 < 0.008

- > 16 -0.25 - > 32 -8 -0.03

Citrobacter freundii

BK-218 Cefixime Cefuroxime Cefaclor Ciprofloxacin

8 2 4 32 0.03

> 16 >4 >32 > 32 0.12

0.25 0.12 1 0.5 5 0.008

- > 16 ->4 ->32 - > 32 - 0.5

BK-218 Cefixime Cefuroxime Cefaclor Ciprofloxacin

16 0.5 8 16 0.015

> 16 >4 >32 > 32 0.03

2 0.12 2 1 _ 16 ->4 ->32 - > 32 - 0.03

BK-218 Cefixime Cefuroxime Cefaclor Ciprofloxacin

0.5 0.25 4 1 < 0.008

2 0.25 8 2 0.03

< 0.06 < 0.008 1 0.5 < 0.008

- 8 - 0.5 -16 -4 -0.03

BK-218 Cefixime Cefuroxime Cefaclor Ciprofloxacln

>16 2 32 > 32 0.015

>16 >4 > 32 > 32 0.03

~0.06 0.12 2 4 _16 ->4 - > 32 - > 32 - 0.06

BK-218 Cefixime Cefuroxime Cefaclor Ciprofloxacm

0.5 0.12 2 1 _ 16 0.25 32 > 32 _ 16 2 32 > 32 0.015

BK-218 Cefixime Cefuroxime Cefaclor Ciprofloxacin

1 < 0.008 1 1 0.015

2 < 0.008 2 1 0.03

(20)

Enterobacter aerogenes

(20)

Enterobacter agglomeram" (10)

Enterobacter cloacae

(20)

Escherichia coli (19)

Klebsiella spp. ~ (30)

Morganella morganii

(10)

Proteus mirabilis

(20)

50 %

90 %

Range

> 16 0.06 - > 4 16 - 32 > 32 _ 32 0.03

> 16 32 >32 0.03

8 _ 32 16 0.015

BK-218 Cefixime Cefuroxlme Cefaclor Ciprofloxacin

2 16 0.25

0.12 - > 16 _ 32 0.015 - 0 . 1 2

.--._.__

Proteus vulgaris

(10)

Providencia rettgeri (10)

Providencia stuartii

(lO)

BK-218 CefixJme Cefuroxtme Cefaclor Ciprofloxaein

Sahnonella enteritidis

BK-218 Cefixime Cefuroxlme Cefaclor Ciprofloxaein

Serratia marceseetls

BK-218 Cefixlme Cefuroxlme Cefaelor Ciprofloxaem

(10)

(20)

Shigella spp. b (10)

~'ersinia enterocolitica

(1o)

Acinetobacter anitratus

(lO)

0.03 4 32 0.12 0.25 0.06 4 0.5 0.015 > 16 0.5 > 32 >32 0.12

BK-218 Cefixlme Cefuroxlme Cefaclor Ciprofloxacin

0.5 0.25 2 1 _4 32 32 0.25

BK-218 Cefixime Chloramphenicol

< 0.015 0.25

BK-218 Cefixime Ampicillin

_ 32 0.12 > 16 >4 > 32 > 32 0.25 0.5 0.25 8 1 0.03 > 16 2 > 32 > 32 0.25 1 0.5 4 2 0.03 16 4 8

16 0.03 > 16 >4 > 32 > 32 0.5

- > 16 -0.12 - > 32 -0.03

2 - > 16 < 0.008 - > 4

0.5 - > 32 4 ->32 0.03 - 0 . 5 0.25 - 0.5 0.03 -0.25 2-8 0.5 - 1 0.015 - 0.03 8 0.12 32 > 32 0.03

- > 16 ->4 - > 32 -0.5

0.25 - 1 0.12 - 1 2-8 0.5 - 2 4 1-8 0.25 - 16 0.015 -0.03 4 ->16 2 ->4 0,25 - > 32 8 ->32 32 > 32 0.25

> 16 >4 > 32 > 32 1

> 16 >4 > 32 > 32 0.25 - 2

BK-218 Cefixime Ce[uroxime Cefaclor Ciprofloxacin

8 >4 > 32 > 32 2

> 16 >4 > 32 > 32 >4

_ 16 4 ->4 2 ->32 _ 32 0.25 - > 4

32

> 32

16 - > 32

beta-lactamase positived (10)

2 < 0.015 -0.12

Moraxella catarrhal& bcta-lactamase negative (10)

1

0.12 - 1

4 > 32 32 0.5

> 16 >4 > 32 > 32 1

16 >4 8 16 0.5

- > 16

BK-218 Cefixime Cefuromme Cefaclor Ciprofloxacin

> 16 >4 > 32 16 2

> 16 >4 > 32 > 32 4

2 >4 32 2 0.25

- > 16

BK-218 Cefixime Cefuroxime Cefaelor Ciprofloxacm

16 >4 >32 >32 0.25

> 16 >4 >32 >32 >4

0.25 >4 1 2 0.12

BK-218 Cefimme Cefuroxime Cefaclor Ciproflo×acin

0.12 >4 i 1 0.12

0.25 >4 1 2 0.25

BK-218 Cefixime Cefuroximc Cefaclor Ciprofloxacin

0.25 >4 0.5 1 0.12

> 16 >4 > 32 > 32 0.25

BK-218 Cefixime Cefuroxime Cefaclor Ciprofloxacin

0.25 4 0.5 1 0.12

BK-218 Cefixime

0.06 0.12

0.25 0.12

0.06 - 1 0.06 - 0.25

BK-218 Cefixime

0.06 0.06

0.06 0.12

0.06 < 0,015 - 0 . 1 2

BK-218 Ce fixime

0.06 0.25

0.12 0.25

0.06 -0.25 0.12 - 0.25

1 >4 16 16 >4

- > 32 - > 32 -2

- > 32 - > 32 - >4 - > 16 ->32 ->32 ->4

< 0.06 - 0.5 2 ->4 0.5 - 4 1-4 0.06 - 0.5 < 0.06 1 < 0.12 < 0.12 0.06

- > 16 ->4 - > 32 - > 32 - >4

5 0.06 50.008 < 0.12 _4 - > 32 - 16 ->4

Streptococcus pneunmoniae c

(lO)

Streptococcus pneunmoniae serogroup A (10)

Streptococcus pneumnoniae serogroup B (10)

a Includes E. faecium (11 strains), E. raffinosus (2 strains), E. gallinarum (2 strains), E. casseliflavus (2 strains), E. durans (1 strain), E. avium (1 strain), E. mundtii (1 strain), and E. hirae (1 strain). Several strains were ampicitlin and/or van comycin-resistant. b Includes S. haemolyticus (10 strains), S. hominis (4 strains), S. shnulans (5 strains), S. saprophyticus (4 strains), S. warneri (6 strains) and S. xylosis (1 strain). c Includes two penicillin-resistant strains ( M I C - 0.12 mg/1).

Vol. 11, 1992

187

Table 4: Susceptibilities to BK-218 and currently available eephalosporins for Escherichia coli C600 containing various recently discovered extended-spectrum beta-lactamases, O m p F mutants and a chromosomal-mediated enzyme. , ,, , ,

Beta-lactamase type Basal Strain (C600) SHV-1 SHV-2 SHV-3 SHV-4 SHV-5 TEM-1 TEM-2 TEM-3 TEM-4 TEM-5 TEM-6 TEM-7 TEM-9 CAZ-2 OmpF + OmpF" Type I (P99)

MIC (mg/1) BK-218

Cefixime

0.5

8 > 16 16 > 16 > 16 0.25 > 16 > 16 > 16 16 4 '4 4 4

1

1 >4 >4 >4 >4 0.5 1 >4 >4 >4 >4 2 >4 >4

0.5 0.5 > 16

0.25 1 >4

most similar to that of so-called first- and secondgeneration cephalosporins

,,,,,

s u c h as c e f a c l o r a n d

eefuroxime axetii (1-3, 5). With such a potency and spectrum, BK-218 could have acceptable therapeutic potential for cutaneous, respiratory and urinary tract infections. However, a significant population of bacteria remains resistant to BK-218 that includes Pseudomonas spp., most Other non-enteric gram-negative bacilli, methicillin-resistant staphylococci, Enterococcus spp., and many species of Enterobacteriaceae (Citrobacter spp., Enterobacter spp., indole-positive Proteae species, Serratia spp., Yersinia enterocolitica). BK-218 does not possess high beta-lactarnase stability for the Richmond-Sykes Type I or IV enzymes and also has elevated MICs (> 16 rag/l) for most strains producing plasmidmediated extended-spectrum beta-lactamases (7-9). BK-218 used as a parenteral cephalosporin would provide the first drug of this class since cephradine having the versatility of dual routes of administration. Since the spectrum of BK-218 is Wider than that of cephradine or cephalexin, this Could be an advantage in the therapy of some organisms routinely resistant to older cephaloSporins.

Cefaclor

Cefotaxime

2

_ 32 > 32 > 32 > 32 1 > 32 > 32 > 32 > 32 4 16 4 4

_ 32 32 > 32 32 ~ 0.25 < 0.25 > 32 > 32 4 2 0.5 2 4

1 2

- 32

> 32

In summary, BK-218 demonstrates a promising activity most like that of cefuroxime and other second-generation cephalosporins. However, human pharmacokinetic and toxicology studies need to be added to these reported microbiologic findings (1) before the clinical role of BK-218 can be judged.

References 1. Szabo I, Barabas J, Tar A, Kiss L, Filep M, Schmidt T, Morossy K, Toth-Martinez B, Barabas G, Hernadi F: In vitro investigation of BK-218, a new oral and parenteral cephalosporin. Antimicrobia[ Agents and Chemotherapy 1990, 34: 349-354. 2. Jones RN, Gerlach EH, Fuchs PC: In vitro antimicrobial activity comparison of cefaclor (compound 99638), cephradine and cephalothin. Journal of Antibiotics 1977, 30: 753--755. 3. Jones RN: Antimicrobial activity, spectrum and pharmacokinetics of old and new orally administered cephems. Antimierobic Newsletter 1988, 5: 1-7. 4. Kamimura T, Koho H, Matsumoto Y, Mine Y, Golo S, Kuwahara S: In vitro and in vivo antibacterial properties of FK 027, a new orally active cephem antibiotic. Antimicrobial Agents and Chemotherapy 1984, 25: 98-104.

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5. O'Cailaghan CH, Sykes RB, Griffiths A, Thornton JE: Cefuroxime, a new cephalosporin antibiotic: activity in vitro. Antimierobial Agents and Chemotherapy 1976, 9: 511-519. 6. Guay DRP, Meatherall RC, Harding GK, Brown GR: Pharmacokinetics of eefixime (CL 284,635; FK 027) in healthy subjects and patients with renal insufficiency. Antimicrobial Agents and Chemotherapy 1986, 30: 483-490. 7. Bush K, Singer SB: Biochemical characteristics of extended broad spectrum beta-lactamases. Infection 1989, 17: 429--431. 8. Jacoby GA, Carreras h Activities of 13-1actam antibiotics against Escherichia coli strains producing extended-spectrum [3-1aetamases. Antimicrobial Agents and Chemotherapy 1990, 34: 858-862. 9. Jones RN, Barry AL: Susceptibility of stably dercpressed beta-lactamase producing strains to imipenem and four quinolones. European Journal of Clinical Microbiology and Infectious Disease 1988, 7: 82-83. 10. National Committee fnr Clinical Laboralory Standards: Standard methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M7-4. NCCLS, Villanova, PA, 1990. 11. National Committee for Clinical Laboratory Standards: Methods for antimicrobiat susceptibility testing of anaerobic bacteria. Tentative standard MM-T2. NCCLS, Villanova, PA, 1989. 12, Jones RN, Gavan TL, Thornsberry C, Fuchs PC, Gerlath EH, Knapp JS, Murray P, Washington JA: Standardization of disk diffusion and agar dilution susceptibility tests for Neisseriagonorrhoeae: interpretive criteria and quality control guidelines for ceftriaxone, penicillin, spectinomycin and tetracycline. Journal of Clinical Microbiology 1989, 27: 2758-2766. 13. Jorgensen JH, Redding JS, Maher LA, Howell AW: Improved medium for antimicrobial susceptibility testing of Haemophilus h~fluenzae. Journal of Clinical Microbiology 1987, 25: 2105-2113. 14. Jorgensen HJ, Maher LA, Howell AW: Use of Haemophilus test medium for broth microdilution antimicrobial susceptibility testing of Streptococcus pneumoniae. Journal of Clinical Microbiology 1990, 28: 430--434.

Eur. J. Clin. Microbiol. Infect. Dis.

In Vitro Evaluation of E-4695, a New Fluoro-Naphthyridine R.N. J o n e s *

Compound E-4695, a C-7 azetidinyl fluoro-naphthyridine, was compared to six structurally related quinoiones and was generally two- to fourfold more active than ciprofloxacin. E-4695 was particularly active against Staphylococcus aureus (MIC90 0.06 mg/I), Staphylococcus haemolyticus (MIC90 0.5 rag/l), Klebsiella spp. (MIC90