ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Sept. 1990, 0066-4804/90/091849-06$02.00/0 Copyright © 1990, American Society for Microbiology
p.
1849-1854
Vol. 34, No. 9
In Vitro Activity of BAY v 3522, a New Cephalosporin for Oral Administration TERI L. HODGES,"2 GEORGE M. ELIOPOULOS,l 2* KARIN KLIMM, AND ROBERT C. MOELLERING, JR."12 Department of Medicine, New England Deaconess Hospital,' and Harvard Medical School,2 Boston, Massachusetts 02215
Received 10 May 1990/Accepted 6 July 1990 The activity of BAY v 3522 was tested against over 500 clinical bacterial isolates and compared with the activities of ampicilln, amoxicillin-clavulanate, cefaclor, cefixime, cefuroxime, cephalexin, and/or ciprofloxacin, erythromycin, and metronidazole. BAY v 3522 activity against staphylococci and streptococci equaled or exceeded those of the other agents. BAY v 3522 exhibited no significant advantage over cefaclor, cefuroxime, or cephalexin against gram-negative bacilli.
BAY v 3522 is a new cephalosporin for oral administration which demonstrated particularly good activity against Staphylococcus spp., Streptococcus pneumoniae, Haemophilus influenzae, and Branhamella catarrhalis (7). This study examined the in vitro activity of BAY v 3522 in comparison with those of other oral antimicrobial agents against approximately 500 bacterial isolates. Most bacteria used in this study were routine clinical isolates collected at the New England Deaconess Hospital, Boston, Mass., or Massachusetts General Hospital, Boston. Additional strains with specific resistance traits have been collected in our laboratory from numerous sources (1). Bacteria were stored frozen at -70°C until used. BAY v 3522 and ciprofloxacin were provided by Pharmaceutical Division of Miles, Inc., West Haven, Conn.; amoxicillin was obtained from Sigma Chemical Co., St. Louis, Mo. Other standard antimicrobial reference powders were generously provided by the following sources: Eli Lilly & Co., Indianapolis, Ind., erythromycin, cephalexin, and cefaclor; Glaxo Laboratories, Ltd., Greenford, United Kingdom, cefuroxime; Lederle Laboratories, Pearl River, N.Y., cefixime; E. R. Squibb & Sons, Inc., Princeton, N.J., ampicillin; Beecham Laboratories, Bristol, Tenn., potassium clavulanate; and Searle Pharmaceuticals Inc., Chicago, Ill., metronidazole. MICs were determined by agar dilution methods (4, 5). Mueller-Hinton agar (BBL Microbiology Systems, Cockeysville, Md.) was used in testing most aerobic and facultative organisms. This was supplemented with 5% defibrinated sheep blood when streptococci and diphtheroids were tested. Kellogg supplement (4) (1% vol/vol) was added to chocolatized blood agar for testing gonococci (GC Agar Base; BBL) and to Mueller-Hinton agar for testing B. catarrhalis. H. influenzae isolates were tested in chocolatized blood agar (Mueller-Hinton agar) supplemented with 1% Vitox (Oxoid Ltd., Basingstoke, England). Bacteroides fragilis and Clostridium perfringens were tested on WilkinsChalgren medium (Oxoid Ltd.); 5% sheep blood was added for other anaerobes. Campylobacter jejuni isolates were tested in brucella agar (Scott Laboratories, Fiskeville, R.I.) supplemented with 10%o sheep blood. Brain-heart infusion agar (Difco Laboratories, Detroit, Mich.) with 7% lysed horse blood was used for testing Helicobacter pylori. Bac*
terial suspensions were prepared from fresh blood or chocolate agar plates in liquid media and applied with a multipronged inoculating device to yield final inocula of approximately 105 CFU per spot for anaerobes (5), C. jejuni, and H. pylori and 104 CFU per spot for other organisms. Plates were incubated at 35°C in room air (most organisms), 5% CO2 (gonococci and H. influenzae), a microaerophilic atmosphere (Campylo-Pak; BBL) (C. jejuni and H. pylori), or an anaerobic atmosphere (Gas-Pak; BBL) (anaerobes). MICs were determined after incubation periods of 24 h (most organisms), 48 h (anaerobes and diphtheroids), or 72 h (H. pylori). On the basis of a comparison of MICs for 90% of the isolates, BAY v 3522 activity against streptococcus groups A, B, C, and G and viridans group streptococci was equivalent to that of ampicillin (Table 1) (BAY v 3522 MIC for 90% of the isolates, 0.03 ,ug/ml for S. pyogenes). BAY v 3522 was more active (2- to 32-fold) than the other cephalosporins against penicillin-resistant pneumococci (five moderately and five highly resistant strains with penicillin MICs of 0.1 to 1.0 ,ug/ml and >1.0 ,ug/ml, respectively). Inhibition of methicillin-susceptible strains of Staphylococcus aureus by BAY v 3522 was equal to that achieved with cefuroxime or amoxicillin-clavulanate. BAY v 3522 was 4- to 16-fold more active than other oral cephalosporins tested against isolates of Enterococcus faecalis and Enterococcus avium but less active (2- to 8-fold) than ampicillin against these organisms. Gram-positive organisms resistant to BAY v 3522 (and to the other cephalosporins tested) included methicillin-resistant strains of S. aureus (MIC for 90% of the isolates 2 64 Vig/ml for all agents) and Staphylococcus epidermidis, E. faecium, and diphtheroids. Among gram-negative strains tested, BAY v 3522 activity against P-lactamase-producing strains of H. influenzae was comparable to that of amoxicillin-clavulanate or cefuroxime and exceeded that of cefaclor. BAY v 3522 was two- to eightfold less active than the other drugs tested against B. catarrhalis (13 of 15 were P-lactamase producing) and less active than cefaclor (two- to eightfold) against tested strains of Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, and Escherichia coli. The six ampicillin-resistant strains of E. coli tested were more resistant to BAY v 3522 (MIC, 8 to 64 ,ug/ml) than the ampicillin-susceptible isolates (MIC, 2 to 32 ,ug/ml). Amoxicillin-clavulanate, cefuroxime, and cefixime all had significantly greater in vitro activities
Corresponding author. 1849
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NOTES
ANTIMICROB. AGENTS CHEMOTHER. TABLE 1. Comparative in vitro activity of BAY v 3522
Organism (no. of isolates)
Staphylococcus aureus, methicillin susceptible (30)
.nii.cMIC (Lg/ml)a
Antibiotic
50%o
90%o
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
0.25-4 0.25-4 0.125-64 2-32 8-32 1-4 2-32
1 1 4 8 16 2 8
2 2 32 16 32 4 16
BAY v 3522 Amoxicillin-clavulanate
0.015-32 0.5-16 0.5-64 0.015->64 0.06->64 0.03->64 0.015->64
1 1 4 8 32 2 8
4 8 16 64 >64 64 >64
Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
0.5-32 0.5-16 0.25-16 0.5-64 4->64 0.5->64 0.5-64
4 4 2 16 64 2 16
32 8 16 32 >64 64 64
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime
0.125->64 0.06-32 0.06->64 0.5->64 4->64 0.5->64 1->64
64 32 64 64 >64 >64 >64
>64 32 >64 64 >64 >64 >64
Range
Staphylococcus epidermidis
Methicillin susceptible (10)
Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin Methicillin resistant (20)
Staphylococcus haemolyticus (30)
BAY v 3522
Cephalexin Staphylococcus hominis (15)
BAY v 3522 Amoxicillin-clavulanate
8 8 16 32 >64 32 64
Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
0.125-8 0.06-8 0.06-16 0.03-32 1->64 0.25-32 1-64
0.25 0.25 0.25 1 8 0.5 4
Streptococcus pyogenes (10)
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
0.03-0.25 0.015-0.25 0.03-0.5 0.5-2 0.125-8 NAb 0.5-2
0.03 0.03 0.06 0.5 0.125 NA 0.5
0.03 0.03 0.06 0.5 0.125 NA 1
Streptococcus agalactiae (10)
BAY v 3522 Amoxicillin-clavulanate
0.125 0.125 0.25 4 0.5 0.06 4
0.25 0.125 0.25 4 1 0.125 4
0.015-0.06 0.03 0.03-0.25 0.25-1 0.125-0.25 0.015-0.03 0.5-2
0.03 0.03 0.06 0.5 0.125 0.015 1
0.06 0.03 0.125 1 0.25 0.03 1
0.06-1 0.03-0.5
0.25 0.125
0.5 0.5
Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin Streptococcus group C (5) and G (5)
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime
Cephalexin Streptococcus, viridans group Penicillin susceptible (10)
BAY v 3522 Amoxicillin-clavulanate
0.03-0.5 0.06-0.125 0.25-0.5 1-8 0.5-4 0.06-0.25 4-8
Continued on following page
VOL. 34, 1990
NOTES
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TABLE 1-Continued Organism (no. of isolates)
Antibiotic
Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin Penicillin resistant (9)
Streptococcus pneumoniae Penicillin susceptible (10)
Penicillin resistant (10)
Enterococcus faecalis Non-high-level gentamicin resistant (20)
High-level gentamicin resistant (15)
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
0.03-0.125 0.03-0.06 0.06-0.25 1-4 0.125-2 0.015-0.5 2-16
0.06 0.03 0.125 1 0.25 0.03 4
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
0.125-4 0.03-2 0.06-4 2->64 1-64 0.5-4 4->64
0.125 0.06 0.125 4 4 0.5 8
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
4-8 0.05-1 1-2 264 32->64 8->64
BAY v 3522 Amoxicillin-clavulanate
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime
BAY v 3522
Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin Enterococcus avium (10)
0.5 4 4 0.25 4
1-8 0.5-8 2-32 264 16-64 8-32 264
Cephalexin Enterococcus faecium (10)
0.125-1 2-16 0.25-4 0.03-0.5 2-16
MIC (Lg/ml)a 509o
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
13-Lactamase positive (5)
Range
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor
4 2 4 >64 32 16 >64
90%o
0.5 16 4 0.25 16 8 2 8 >64 64 16 >64 0.125 0.06 0.125 2 1 0.25 16 2 2 4 >64 64 4 64 8 1 1 >64 >64 >64
264
4 1 1 64 >64 >64 >64
4-16 0.5-1 0.5-2 264 >64 >64 >64
4 1 1 >64 >64 >64 >64
16 1 2 >64 >64 >64 >64
32 2 2 64 >64 >64 >64
64 4 8 >64 >64 >64 >64
>64
4 0.5-1 1-2 64 >64 >64 >64 8-64 1-4 1-8
.64 >64 >64 >64
0.5-16 0.5-2 0.5-1 0.5-64
1 0.5 0.5 4
4 1 1 16
Continued on following page
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ANTIMICROB. AGENTS CHEMOTHER.
NOTES
TABLE 1-Continued Organism (no. of isolates)
MIC (,Lg/ml)a
*
AOnio Range (,PfiYimp
>.#;A 8->64
9
--f#M
-->#; >64
Cefuroxime Cephalexin
8->64 8>,64
32 8
>64 >64
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
8->64 2->64 4->64
4->64 16->64
32 4 8 >64 >64 16 64
>64 >64 >64 >64 >64 >64 >64
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
1->64 0.06->64 0.06->64 8->64 2->64 0.25->64 2->64
4 64 >64 64 >64 2 16
>64 >64 >64 >64 >64 >64 >64
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
1-4 1-2
Diphtheroids Corynebacterium JK group (10)
Non-JK group (15)
Haemophilus influenzae ,B-Lactamase positive (15)
P-Lactamase negative (15)
Branhamella catarrhalis (15)
Neisseria gonorrhoeae Penicillin susceptible (10)
Penicillin resistant (10)
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
16-64 4-32 0.03-0.125 0.5-2 32->64 1-4 0.5-2 0.5-2
4-32 0.03-0.25 1-2 32->64
2 2 64 4 0.06 1 64
2 2 64 16 0.06 1 >64
2 1 0.5 8 0.06 1 64
4 1 0.5 16 0.125 2 >64
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
0.5-8 0.06-0.5 C0.008-8 1-8 0.06-0.5 0.5-2 2-4
2 0.25 2 2 0.25 1 4
8 0.5 4 4 0.5 1 4
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
0.25-8 0.06-1 0.03-1 1-64 C0.008-0.03 0.03-1 1-16
2 0.5 0.25 4
C0.008 0.25 4
8 1 1 64 0.03 1 16
4 1 16 C0.008 0.125 4
16 2 >64 0.015 1 16
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefixime Cefuroxime
Cephalexin Klebsiella pneumoniae (20)
>64 >64
BAY v 3522 Amoxicillin-clavulanate
Ampicillin Cefaclor
2-16 0.5-2
4->64 S0.008-0.03 0.015-1 1-16 1-16 2-16 16->64 1-16
4 4 32 2
8 4 64 8
Continued on following page
NOTES
VOL. 34, 1990
1853
TABLE 1-Continued Organism (no. of isolates)
AniitcMIC (>Lg/ml)a Ato Range
90%
Cefaclor Cefixime Cefuroxime Cephalexin
1-4 0.03-0.5 2-16 4-16
2 0.06 4 8
2 0.125 8 8
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefixime Cefuroxime Cephalexin
2->64 4-64 16->64 1-32 0.03-0.05 0.03-1 2-8 4-16
32 8 64 2 0.06 0.03 4 8
>64 64 >64 32 0.125 0.06 8 8
Escherichia coli (30)
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
2-64 2-32 1->64 1-16 0.125-1 1-16 4-16
8 4 2 4 0.5 4 8
Proteus mirabilis (30)
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
Klebsiella
oxytoca
(10)
Bacteroides fragilis (30)
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin Metronidazole
2-32 1-8 1-16 2-8
C0.008-0.03 0.5-16 16-64 32->64 1-16 2->64 264 32->64
.64 >64 1-2
8 1 2 4 0.015 2 32 >64 1 32 >64 >64 >64 >64 1
32 16 >64 4 0.5 8 16 16 4 8 4 0.03 4 64 >64 8 >64 >64
>64 >64 >64 2
Bacteroides melaninogenicus (9)
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin Metronidazole
0.125-64 0.06-1 0.125-64 2->64 0.125-64 0.06->64 1-16 8->64
0.5 0.5 1 16 0.5 0.25 1 8
16 0.5 16 64 2 32 4 >64
Anaerobic cocci (8)
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin Metronidazole
0.5-64 0.25-2 0.25-2 8->64 4->64 0.25-8 8->64 1->64
2 0.5 0.5 16 32 2 16 8
16 1 0.5 >64 >64 8 >64 8
Clostridium perfringens (9)
BAY v 3522 Amoxicillin-clavulanate Ampicillin Cefaclor Cefixime Cefuroxime Cephalexin
5s0.008-0.06 64
>64 2 8
0.03 0.03 0.03 2 4 2 8 >64 2 >64
Continued on following page
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ANTIMICROB. AGENTS CHEMOTHER.
NOTES
TABLE 1-Continued Organism (no. of isolates)
Helicobacter pylori (30)
Antibiotic
MIC (,u g/ml)a Range
Cefaclor Cefixime Cefuroxime Cephalexin Erythromycin
0.5-4
BAY v 3522 Ampicillin Ciprofloxacin
0.125-8 0.06-1 0.25-1
16->64 8->64 16->64
.64
509o
>64 32 >64 >64 1
1 0.125 0.5
90%
>64 >64 >64 >64 4
4 1 0.5
a 50o and 90%o, MIC for 50 and 90% of isolates, respectively. b NA, Not available.
against gonococci than BAY v 3522. BAY v 3522 was inactive against 10 clinical isolates of K. pneumoniae producing plasmid-mediated TEM-type ceftazidime-hydrolyzing enzymes. Other members of the family Enterobacteriaceae and Pseudomonas species were not tested because the drug has not shown significant activities against these (7). BAY v 3522 inhibited tested strains of H. pylori but was two- to eightfold less active than ampicillin or ciprofloxacin. C. jejuni isolates were resistant (MIC 2 64 ,ug/ml). By agar dilution techniques, BAY v 3522 and the other tested cephalosporins were inactive against B. fragilis at concentrations c 64 ,ug/ml. B. fragilis resistance to BAY v 3522 was confirmed by anaerobic broth dilution techniques (5) for five strains. Against Bacteroides melaninogenicus and anaerobic cocci, the MIC for 90%o of the isolates of BAY v 3522 was 16 ,ug/ml. Orally administered cephalosporins and penicillins are widely used in treating skin and soft tissue, respiratory, and urinary tract infections. Against streptococci and staphylococci, organisms frequently responsible for skin and soft tissue infections, BAY v 3522 was as active as the other oral agents tested. Antimicrobial resistance patterns which have emerged among common respiratory pathogens in recent years include penicillin resistance among pneumococci (2) and P-lactamase production by B. catarrhalis (3) and H. influenzae (6). An ideal agent for empiric therapy of respiratory infections would be active against such resistant strains. BAY v 3522 activity against penicillin-resistant strains of pneumococci was equal to or exceeded those of the other agents tested. In addition, BAY v 3522 exhibited activity against B. catarrhalis and H. influenzae, although some agents were more potent against these. If supported by in vivo testing, BAY v 3522 may have a role in treating infections caused by such pathogens.
Finally, BAY v 3522 was significantly more active against E. faecalis than the other cephalosporins tested. It remains to be determined whether BAY v 3522 may be useful in treating penicillin-intolerant patients with uncomplicated urinary tract infections caused by E. faecalis. This study was supported by a grant from the Pharmaceutical Division of Miles, Inc., West Haven, Conn. LITERATURE CITED 1. Allan, J. D., Jr., G. M. Eliopoulos, E. Reiszner, and R. C. Moellering, Jr. 1987. In vitro activities of ICI 194008 and ICI 193428, two new cephem antimicrobial agents. Antimicrob. Agents Chemother. 31:1997-2001. 2. Feldman, C., J. M. Kaflenbach, S. D. Miller, J. R. Thorburn, and H. J. Koornhof. 1985. Community-acquired pneumonia due to penicillin-resistant pneumococci. N. Engl. J. Med. 313:615-617. 3. Luman, I., R. W. Wilson, R. J. Wallace, Jr., and D. R. Nash. 1986. Disk diffusion susceptibility of Branhamella catarrhalis and relationship of 3-lactam zone size to 3-lactamase production. Antimicrob. Agents Chemother. 30:774-776. 4. National Committee for Clinical Laboratory Standards. 1988. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically (2nd ed.). Tentative standard M7-T2. National Committee for Clinical Laboratory Standards, Villanova, Pa. 5. National Committee for Clinical Laboratory Standards. 1989. Methods for antimicrobial susceptibility testing of anaerobic bacteria (2nd ed.). M11-T2. National Committee for Clinical Laboratory Standards, Villanova, Pa. 6. Williams, J. D., and F. Moosdeen. 1986. Antibiotic resistance in Haemophilus influenzae: epidemiology, mechanisms, and therapeutic possibilities. Rev. Infect. Dis. 8:S555-S561. 7. Wise, R., J. M. Andrews, J. P. Ashby, and D. Thornber. 1990. In vitro activity of Bay v 3522, a new cephalosporin, compared with activities of other agents. Antimicrob. Agents Chemother. 34: 813-818.