ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1995, p. 533–538 Vol. 39, No. 2 0066-4804/95/$04.00ϩ0 Copyright ᭧ 1995, American Society for Microbiology

Antibacterial Activities of Cefprozil Compared with Those of 13 Oral Cephems and 3 Macrolides JOAN C. FUNG-TOMC,* ELIZABETH HUCZKO, TERRY STICKLE, BEATRICE MINASSIAN, BENJAMIN KOLEK, KENNETH DENBLEYKER, DANIEL BONNER, AND ROBERT KESSLER Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492

Received 15 August 1994/Returned for modification 17 October 1994/Accepted 28 November 1994

Thirteen oral cephems (cefprozil, loracarbef, cefaclor, cefuroxime axetil, cefpodoxime proxetil, cefetamet pivoxil, cefixime, cefdinir, cefadroxil, cephradine, cephalexin, cefatrizine, and cefroxadine), the cephalosporin class representative cephalothin, cefazolin, and the macrolides erythromycin, clarithromycin, and azithromy- cin were compared for their antibacterial activities against 790 recent clinical isolates. These oral agents differed in their spectra and antibacterial potencies against community-acquired pathogens.

Oral cephalosporins have been useful in the treatment of Laboratories, Pearl River, N.Y.; cefetamet was from Roche community-acquired infections such as pharyngitis, otitis me- Laboratories, Nutley, N.J.; cefuroxime axetil was from Glaxo dia, bronchitis, and skin and skin structure infections as well as Pharmaceuticals, Research Triangle Park, N.C.; clarithromycin uncomplicated urinary tract infections. In recent years several was from Abbott Laboratories, North Chicago, Ill.; and new cephem derivatives which differ in their antibacterial spec- azithromycin was from Pfizer Inc., Groton, Conn. tra and pharmacokinetic profiles have been introduced. In this MICs were determined by an agar dilution method outlined study we compared the antibacterial activities of seven new by the National Committee for Clinical Laboratory Standards oral cephems (cefprozil, loracarbef, cefuroxime axetil, cefpo- (10). Mueller-Hinton agar was used except with Streptococcus doxime proxetil, cefetamet pivoxil, cefixime, and cefdinir) with pyogenes (supplemented with 5% sheep blood) and Haemophi- those of six older oral cephalosporins (cefaclor, cefadroxil, lus influenzae (Haemophilus Test Medium Agar). For suscep- cephradine, cephalexin, cefatrizine, and cefroxadine). Since tibility testing of macrolides, the Mueller-Hinton agar medium cephalothin can be used in susceptibility testing to represent was adjusted to pH 7.3. The final inocula contained approxi- many oral cephems (cephapirin, cephradine, cephalexin, cefa- mately 1 ϫ 104 to 3 ϫ 104 CFU per spot. Susceptibility testing clor, cefadroxil, cefuroxime, cefpodoxime, cefprozil, and lora- of the cephems against S. pneumoniae was determined by using carbef) in their activities against staphylococci and streptococci a broth microdilution method and Mueller-Hinton broth, other than Streptococcus pneumoniae (10), the antibacterial which was supplemented with 3% laked horse blood, and final activities of the oral cephems were compared with those of this inocula of 3 ϫ 105 to 5 ϫ 105 CFU/ml. Macrolide testing cephalosporin class representative and with that of cefazolin. against S. pneumoniae was done with Mueller-Hinton agar, pH Cefazolin is considered to have a nearly identical spectrum of 7.3, supplemented with 5% sheep blood. Test plates were in- activity and susceptibility test results as cephalothin against cubated at 35ЊC in ambient air (5% CO for H. influenzae) for staphylococci (10). The macrolides erythromycin, clarithromy- 2 18 h (24 h for streptococci and H. influenzae). The MIC was cin, and azithromycin are used to treat some of the same defined as the lowest drug concentration that prevented visible clinical syndromes (respiratory tract and skin and skin struc- growth or yielded fewer than six discrete colonies. ture infections) as the oral cephems, and they were also in- As indicated in Table 1, of the oral cephems, only cefprozil cluded in this study. and cefdinir have MICs at which 90% of the isolates are in- A total of 790 bacterial strains were tested in this study. hibited (MIC s) of Յ1 ␮g/ml against Staphylococcus aureus.In Most were obtained from clinical trials between 1987 and 1992. 90 general, the MIC s of these cephalosporins were two- to four- In addition, the S. pneumoniae strains which were intermedi- 90 fold higher against ␤-lactamase-producing strains than against ately susceptible or resistant to penicillin were kindly provided nonproducing strains of S. aureus. The MIC s for ␤-lacta- by several investigators (P. Bourbeau, R. Hakenbeck, J. Hin- 90 mase-producing S. aureus are 2 ␮g/ml for cefatrizine; 4 ␮g/ml dler, J. Jorgensen, D. Shungu, and M. Weinstein). The strains for cefuroxime and cefpodoxime; 8 ␮g/ml for cefaclor, loracar- were preserved in Trypticase soy broth supplemented with bef, and cefadroxil; and 16 ␮g/ml for cephradine, cephalexin, 15% glycerol and were kept frozen at 70 C. Cefprozil, ce- Ϫ Њ and cefroxadine. Cefixime and cefetamet are considered inac- fadroxil, cefatrizine, cephradine, cefdinir, and erythromycin tive against S. aureus. Except for cefprozil and cefdinir, cefa- were prepared at Bristol-Myers Squibb, Syracuse, N.Y. Cefa- zolin and the cephalosporin class representative cephalothin clor, cephalexin, cephalothin, cefazolin, and loracarbef were (MIC s of 0.5 to 1 ␮g/ml) were more active against staphylo- from Eli Lilly & Co., Indianapolis, Ind.; cefroxadine was from 90 cocci than the oral cephalosporins which they represent. In Ciba Pharmaceutical Co., Summit, N.J.; cefpodoxime was from fact, the cephalothin and cefazolin MICs for all 195 staphylo- the Upjohn Co., Kalamazoo, Mich.; cefixime was from Lederle coccal strains were Յ1 ␮g/ml, whereas MICs of Ն32 ␮g/ml were observed for 2 strains for cephradine, 11 strains for cephalexin, and 6 strains for cefroxadine. In addition, MICs of * Corresponding author. Mailing address: Department of Microbi- 16 ␮g/ml were observed for 1 strain for cefaclor, 2 strains for ology—104, 5 Research Pkwy., Wallingford, CT 06457. Phone: (203) loracarbef, 4 strains for cefadroxil, 14 strains for cephradine, 49 284-6370. Fax: (203) 284-6771. strains for cephalexin, and 75 strains for cefroxadine. These

533 534 NOTES ANTIMICROB.AGENTS CHEMOTHER.

TABLE 1. In vitro activities of 13 oral cephems, cephalothin, cefazolin, and macrolides

a Bacterial species MIC (␮g/ml) Drug (no. tested) Range 50% 90% S. aureus, BLAϪb,d (54) Cefprozil 0.13–1 0.5 0.5 Cefaclor 0.25–4 1 2 Loracarbef 0.5–4 1 2 Cefadroxil 0.5–8 2 4 Cephradine 0.5–8 2 8 Cephalexin 1–16 4 8 Cefatrizine 0.25–1 0.5 1 Cefroxadine 1–8 4 8 Cefuroxime 0.13–2 1 2 Cefpodoxime 0.25–4 2 4 Cefetamet 0.5–64 32 64 Cefixime 2–32 8 16 Cefdinir Յ0.03–1 0.25 0.5 Cephalothin 0.06–0.5 0.25 0.25 Cefazolin 0.06–0.5 0.25 0.5 Erythromycin Յ0.016–Ͼ32 0.13 0.13 Clarithromycin Յ0.016–Ͼ32 0.06 0.06 Azithromycin 0.03–Ͼ32 0.13 0.13 S. aureus, BLAϩc,d (141) Cefprozil 0.25–2 1 1 Cefaclor 0.5–16 4 8 Loracarbef 0.5–16 4 8 Cefadroxil 1–16 8 8 Cephradine 1–32 8 16 Cephalexin 2–64 8 16 Cefatrizine 0.5–4 1 2 Cefroxadine 4–32 16 16 Cefuroxime 1–4 4 4 Cefpodoxime 1–4 4 4 Cefetamet 16–64 64 64 Cefixime 2–32 16 16 Cefdinir 0.25–1 0.5 1 Cephalothin 0.25–0.5 0.5 0.5 Cefazolin 0.25–1 0.5 1 Erythromycin 0.06–Ͼ32 0.13 16 Clarithromycin 0.06–Ͼ32 0.06 8 Azithromycin 0.06–Ͼ32 0.13 16 S. pyogenes (105) Cefprozil 0.016–0.06 0.03 0.03 Cefaclor 0.06–0.13 0.13 0.13 Loracarbef 0.03–0.13 0.06 0.06 Cefadroxil 0.06–0.25 0.13 0.13 Cephradine 0.13–0.5 0.25 0.5 Cephalexin 0.25–2 0.5 1 Cefatrizine 0.016–0.13 0.03 0.06 Cefroxadine 0.13–0.25 0.25 0.25 Cefuroxime Յ0.008–0.03 0.016 0.016 Cefpodoxime Յ0.008–0.016 0.016 0.016 Cefetamet 0.03–0.06 0.03 0.06 Cefixime 0.06–0.25 0.13 0.13 Cefdinir Յ0.008–0.03 0.016 0.016 Cephalothin 0.06–0.5 0.13 0.25 Cefazolin 0.06–0.25 0.13 0.25 Erythromycin 0.016–4 0.03 0.03 Clarithromycin Յ0.008–4 0.016 0.016 Azithromycin 0.016–Ͼ16 0.03 0.03

S. pneumoniae, penicillin susceptible (26) Penicillin Յ0.008–0.03 Յ0.008 0.016 Cefprozil 0.016–0.13 0.06 0.13 Cefaclor 0.13–0.5 0.25 0.5 Loracarbef 0.13–1 0.5 1 Cefadroxil 0.25–4 1 2 Cephradine 0.13–2 0.5 2 Cephalexin 1–8 2 4 Cefatrizine 0.03–1 0.13 0.25 Cefroxadine 0.5–4 1 2 Cefuroxime Յ0.008–0.06 0.016 0.03 Continued on following page VOL. 39, 1995 NOTES 535

TABLE 1—Continued

a Bacterial species MIC (␮g/ml) Drug (no. tested) Range 50% 90% Cefpodoxime Յ0.008–0.06 0.016 0.06 Cefetamet Յ0.03–0.5 0.25 0.5 Cefixime Յ0.03–0.5 0.13 0.25 Cefdinir 0.016–0.25 0.06 0.13 Cephalothin NDe Cefazolin ND Erythromycin Յ0.008–0.03 0.016 0.016 Clarithromycin Յ0.008–0.016 Ͻ0.008 Ͻ0.008 Azithromycin Յ0.008–0.03 0.016 0.016 S. pneumoniae, penicillin intermediate (15) Penicillin 0.13–1 0.25 0.5 Cefprozil 0.25–4 0.5 4 Cefaclor 0.25–64 1 32 Loracarbef 0.5–64 4 64 Cefadroxil 2–64 4 32 Cephradine 2–128 4 32 Cephalexin 4–128 8 64 Cefatrizine 0.25–4 0.25 4 Cefroxadine 2–128 8 32 Cefuroxime Յ0.06–4 0.5 4 Cefpodoxime Յ0.06–4 0.25 4 Cefetamet 0.25–128 2 32 Cefixime 0.5–32 2 16 Cefdinir Յ0.06–4 0.25 4 Cephalothin ND Cefazolin ND Erythromycin Յ0.008–Ͼ16 0.03 8 Clarithromycin Յ0.008–Ͼ16 0.016 2 Azithromycin 0.016–Ͼ16 0.03 4 S. pneumoniae, penicillin resistant (15) Penicillin 2–16 2 4 Cefprozil 1–Ͼ16 8 16 Cefaclor 8–Ͼ128 64 128 Loracarbef 16–Ͼ128 128 Ͼ128 Cefadroxil 16–Ͼ128 128 128 Cephradine 16–Ͼ128 128 Ͼ128 Cephalexin 64–Ͼ128 128 Ͼ128 Cefatrizine 8–64 32 32 Cefroxadine 4–Ͼ128 32 128 Cefuroxime 1–8 4 8 Cefpodoxime 0.5–4 2 2 Cefetamet 4–128 32 64 Cefixime 8–32 16 32 Cefdinir 2–16 8 16 Cephalothin ND Cefazolin ND Erythromycin Յ0.008–Ͼ16 0.5 Ͼ16 Clarithromycin Յ0.008–Ͼ16 0.25 Ͼ16 Azithromycin Յ0.008–Ͼ16 0.5 Ͼ16 H. influenzae, BLAϪ (94) Cefprozil 1–8 2 8 Cefaclor 1–16 4 8 Loracarbef 1–8 2 4 Cefadroxil 8–128 64 128 Cephradine 16–Ͼ128 64 128 Cephalexin 8–128 32 64 Cefatrizine 2–16 4 8 Cefroxadine 8–64 16 32 Cefuroxime 0.25–2 0.5 1 Cefpodoxime Յ0.06–0.25 Ͻ0.06 0.13 Cefetamet 0.13–1 0.13 0.25 Cefixime Յ0.06 Ͻ0.06 Ͻ0.06 Cefdinir 0.25–1 0.5 1 Cephalothin 1–8 4 8 Cefazolin 1–32 8 8 Erythromycin 0.13–16 4 8 Clarithromycin 0.13–16 8 16 Azithromycin 0.25–4 2 2 Continued on following page 536 NOTES ANTIMICROB.AGENTS CHEMOTHER.

TABLE 1—Continued

a Bacterial species MIC (␮g/ml) Drug (no. tested) Range 50% 90% H. influenzae, BLAϩ (41) Cefprozil 2–8 4 8 Cefaclor 2–16 4 8 Loracarbef 1–8 4 4 Cefadroxil 8–Ͼ128 64 64 Cephradine 16–Ͼ128 64 128 Cephalexin 8–64 32 64 Cefatrizine 2–64 8 16 Cefroxadine 16–Ͼ128 32 64 Cefuroxime 0.5–1 1 1 Cefpodoxime Յ0.06–0.25 Ͻ0.06 Ͻ0.06 Cefetamet 0.13–0.5 0.25 0.25 Cefixime Յ0.06–0.13 Ͻ0.06 Ͻ0.06 Cefdinir 0.25–2 0.5 0.5 Cephalothin 1–16 4 8 Cefazolin 4–32 8 16 Erythromycin 0.5–16 4 8 Clarithromycin 1–16 8 8 Azithromycin 0.25–4 2 2

M. catarrhalis, BLAϪ (18) Cefprozil 0.5–2 0.5 1 Cefaclor 0.25–1 0.25 0.5 Loracarbef 0.13–2 0.25 0.5 Cefadroxil 1–8 4 4 Cephradine 2–4 4 4 Cephalexin 1–4 4 4 Cefatrizine 0.25–2 0.25 1 Cefroxadine 1–4 2 2 Cefuroxime 0.25–4 0.5 0.5 Cefpodoxime 0.06–0.5 0.13 0.25 Cefetamet 0.5–1 0.5 1 Cefixime Յ0.06–0.25 Ͻ0.06 0.25 Cefdinir 0.06–0.13 0.06 0.13 Cephalothin 0.5–4 1 1 Cefazolin 0.25–2 0.5 1 Erythromycin Յ0.016–0.06 0.06 0.06 Clarithromycin Յ0.016–0.06 0.03 0.03 Azithromycin Յ0.016 Ͻ0.016 Ͻ0.016

M. catarrhalis, BLAϩ (77) Cefprozil 0.25–8 1 2 Cefaclor 0.25–4 1 2 Loracarbef 0.13–8 1 2 Cefadroxil 1–32 4 4 Cephradine 1–64 4 4 Cephalexin 1–32 4 8 Cefatrizine 0.25–4 1 2 Cefroxadine 1–8 2 4 Cefuroxime 0.13–8 1 2 Cefpodoxime 0.06–1 0.25 0.5 Cefetamet 0.5–1 0.5 1 Cefixime Յ0.06–0.5 0.13 0.5 Cefdinir 0.06–0.25 0.13 0.25 Cephalothin 0.5–8 4 8 Cefazolin 0.25–16 4 8 Erythromycin Յ0.016–0.13 0.06 0.06 Clarithromycin Յ0.016–0.06 0.03 0.03 Azithromycin Յ0.016–0.03 Ͻ0.016 Ͻ0.016

E. coli (106) Cefprozil 0.5–16 1 4 Cefaclor 0.5–8 1 2 Loracarbef Յ0.25–2 0.5 1 Cefadroxil 4–32 8 8 Cephradine 4–32 8 16 Cephalexin 2–16 4 8 Cefatrizine 0.5–16 1 4 Cefroxadine 2–16 4 4 Cefuroxime 0.5–4 2 2 Cefpodoxime Յ0.25–0.5 Ͻ0.25 0.5 Continued on following page VOL. 39, 1995 NOTES 537

TABLE 1—Continued

a Bacterial species MIC (␮g/ml) Drug (no. tested) Range 50% 90% Cefetamet Յ0.25–1 0.5 0.5 Cefixime Յ0.008–0.5 0.016 0.25 Cefdinir Յ0.25–1 Ͻ0.25 0.5 Cephalothin 1–32 8 16 Cefazolin 0.5–32 1 4

K. pneumoniae (98) Cefprozil 0.5–128 1 8 Cefaclor 0.5–64 1 4 Loracarbef Յ0.25–32 0.5 1 Cefadroxil 4–32 8 16 Cephradine 4–128 8 64 Cephalexin 8–64 16 32 Cefatrizine Յ0.25–128 0.5 2 Cefroxadine 2–128 4 8 Cefuroxime 1–32 2 16 Cefpodoxime Յ0.25–32 Ͻ0.25 0.5 Cefetamet Յ0.25–2 Ͻ0.25 0.25 Cefixime 0.016–0.5 0.03 0.25 Cefdinir Յ0.25–8 Ͻ0.25 0.5 Cephalothin 2–Ͼ128 4 16 Cefazolin 1–128 2 4

a 50% and 90%, MIC50 and MIC90, respectively. b BLAϪ, strains did not produce ␤-lactamase. c BLAϩ, strains produced ␤-lactamase. d All strains were methicillin susceptible. e ND, not determined.

results indicate that cephalothin may not be the best class observed with cefatrizine, cefixime, cefaclor, and cefetamet; representative for the cephalosporins. In general, the best class MIC90sof1and2␮g/ml were observed with loracarbef, ce- representative should be the least active drug within the class fadroxil, cephradine, and cefroxadine; and a MIC90 of 4 ␮g/ml (2). Moreover, our results show that the antistaphylococcal was observed with cephalexin. Against penicillin-intermediate activities of the oral cephems differ and can be determined (penicillin MICs of 0.1 to 1 ␮g/ml) strains of pneumococci, the only by testing the individual agents. MIC50s and MIC90s of cefprozil, cefatrizine, cefuroxime, cef- Macrolide-resistant (erythromycin MIC of Ն8 ␮g/ml) strains podoxime, and cefdinir were Յ0.5 and 4 ␮g/ml (2 ␮g/ml for of S. aureus were more frequently encountered among strains cefpodoxime), respectively. For the other oral cephalosporins, producing ␤-lactamase (17 of 141 strains) than among strains the MIC90s against penicillin-intermediate pneumococci were not producing the enzyme (1 of 54 strains). Moreover, three Ն16 ␮g/ml. For the most part, the oral cephems were inactive additional strains of ␤-lactamase-producing S. aureus were in- (MIC90sofϾ8␮g/ml) against penicillin-resistant (penicillin termediately susceptible to erythromycin (MICs of 1 and 2 MICs of Ͼ1 ␮g/ml) strains. ␮g/ml) but were susceptible to clarithromycin (MIC of 0.5 ␮g/ml) Whereas none of the 26 penicillin-susceptible pneumococcal and azithromycin (MIC of 1 ␮g/ml). These three S. aureus strains were resistant to the macrolides, 2 of the 15 penicillin- strains with decreased susceptibility to erythromycin were in- intermediate and 5 of the 15 penicillin-resistant pneumococci ducibly resistant to erythromycin, as demonstrated by the D- were resistant to erythromycin (MIC of Ն4 ␮g/ml). Two addi- shaped inhibition zone around a clindamycin disk placed near tional penicillin-resistant pneumococcal strains were interme- an erythromycin disk (11). The 10% prevalence of erythromy- diately susceptible to erythromycin (MIC of 2 ␮g/ml). The cin resistance among methicillin-susceptible S. aureus organ- incidences of erythromycin-resistant S. pneumoniae differ geo- isms observed in this study correlates with resistance frequen- graphically; however, as observed in this study, the incidence cies previously reported by others (3, 9). may be high among penicillin-resistant strains. Erythromycin

Except for cephalexin (MIC90 of 1 ␮g/ml), all of the cephems resistance rates of 20 to 45% have been reported among pen- had MIC90sofϽ1␮g/ml against S. pyogenes. Two of 105 strains icillin-resistant pneumococci (5, 8, 12). of S. pyogenes were resistant to erythromycin, and a third strain Cefixime and cefpodoxime were particularly active against was inducibly resistant (erythromycin and azithromycin MICs H. influenzae (MIC90sofϽ0.06 to 0.13 ␮g/ml). Cefdinir and of 1 ␮g/ml; clarithromycin MIC of 0.5 ␮g/ml). Generally, this the orally absorbable ester prodrugs cefetamet and cefuroxime lower incidence of erythromycin resistance among S. pyogenes showed good activities against H. influenzae, with MIC90sof (group A) organisms has also been reported for groups B, C, Յ1␮g/ml. The cefprozil, cefaclor, and loracarbef MIC90s were and G of beta-hemolytic streptococci (9). Much higher inci- 4to8␮g/ml against ␤-lactamase-producing and nonproducing dences (30 to 80%) have been reported in countries where strains of H. influenzae. The older cephalosporins lacked ac- erythromycin is widely used (9, 11). tivity against this organism. Azithromycin was the most active

Cefprozil, cefuroxime, cefpodoxime, and cefdinir had MIC90s of the macrolides against H. influenzae, with MIC90sof2␮g/ of Յ0.13 ␮g/ml against penicillin-susceptible (penicillin MIC ml, in contrast to 8 ␮g/ml for erythromycin and clarithromycin. of Ͻ0.1 ␮g/ml) strains of S. pneumoniae. MIC90s for penicillin- The MIC90s of cefpodoxime, cefetamet, cefixime, and cefdi- susceptible pneumococcal strains of 0.25 and 0.5 ␮g/ml were nir against ␤-lactamase-producing strains of Moraxella ca- 538 NOTES ANTIMICROB.AGENTS CHEMOTHER.

tarrhalis were Յ1 ␮g/ml; the MIC90s of cefprozil, cefaclor, active against gram-negative bacteria (E. coli, K. pneumoniae, loracarbef, cefadroxil, cephradine, cefatrizine, cefroxadine, M. catarrhalis, and H. influenzae). Cefuroxime was also very and cefuroxime were 2 to 4 ␮g/ml. These cephems were gen- active against H. influenzae. The macrolides were uniformly erally two-to fourfold less active against ␤-lactamase-pro- active against M. catarrhalis and against most strains of S. ducing strains of M. catarrhalis than against strains which do pyogenes. Resistance to the macrolides was common among S. not produce the enzyme. The MIC90s of cephalothin and ce- aureus organisms and in penicillin-intermediate and penicillin- fazolin were 8 ␮g/ml against ␤-lactamase-producing M. ca- resistant pneumococcal strains. tarrhalis, which was eightfold higher than the MIC90s for non- producing strains. The macrolides were uniformly active REFERENCES against M. catarrhalis. 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