45

DIAGN MICROBIOL INFECT DIS 1990;13:45-49

ANTIMICROBIAL SUSCEPTIBILITY

Comparative in vitro Activity of Cefoperazone and Various Combinations of Cefoperazone/ Sulbactam Cynthia C. Knapp, Juan Sierra-Madero, and John A. Washington

Cefoperazone with 2 and 4 p,g/ml of sulbactam and in a 2:1 ratio was tested against 1258 clinical isolates of Gram-positive and Gram-negative bacteria, as well as against Gram-negative bacilli that had stably derepressed Type I ~-lactamase or that were hyperproductive of non-Type I ~-lactamases. The 2:1 cefoperazone/sulbactam combination was the most potent combination tested. With this combination cefoperazone minimum inhibitory concentrations (MICs) of 27 of 40 (67%) of the clinical isolates of Pseudomonas species and 64 of 67 (95%) of clinical isolates of the Enterobacteriaceae were reduced from >~64 ~,g/ml by at least two-fold. In contrast, cefoperazone

MICs of >~64 ~,g/ml remained unchanged for 26 (65~7c) and 24 (60~ ) of Pseudomonas species and 35 (52%) and 30 (45%) of the Enterobacteriaceae in the presence of 2 and 4 ~g/ml of sulbactam, respectively. Cefoperazone/sulbactam in the 2:1 ratio was also the most active combination against the mutants derepressed for Type I ~-lactamase. Although the 2:1 combination of cefoperazone/sulbactam had the greatest potency in vitro, it remains to be seen whether this combination is predictive of clinical outcome from treatment of cefoperazoneresistant Gram-negative bacilli with cefoperazone/sulbactam.

INTRODUCTION

foperazone-resistant species of the Enterobacteriaceae that are typically associated with derepression of Type I [3-1actamase. Little or no synergistic activity occurred against such cefoperazone-resistant strains w h e n sulbactam at a concentration of 2 or 4 ~g/ml was combined with cefoperazone (Jones et al., 1987). On the basis of their data and the respective pharmacokinetics of cefoperazone and sulbactam, Jones et al. (1987) have r e c o m m e n d e d testing the combination of cefoperazone/sulbactam in a 2:1 ratio. The objectives of this study were to examine further the relative activity of cefoperazone combined with sulbactam in fixed concentrations of 2 and 4 p,g/ml and in a 2:1 ratio.

Sulbactam is an irreversible ("suicide") inhibitor of f3-1actamases (Bush, 1988) that usually produces a synergistic interaction w h e n combined with 13-1actams against bacteria with plasmid-mediated 13-1actamases but that may also act synergistically with e x t e n d e d spectrum penicillins against some Gramnegative bacilli with chromosomally-mediated Type I f3-1actamase (Jacobs et al., 1986). Jones et al. (1987) have d e m o n s t r a t e d synergistic activity between cef o p e r a z o n e and sulbactam (in 2:1 ratio) against ceFrom the Department of Microbiology, The Cleveland Clinic Foundation, Cleveland, Ohio. Address reprint requests to: John A. Washington, M.D., Chairman, Department of Microbiology, The Cleveland Clinic Foundation, One Clinic Center, 9500 Euclid Avenue, Cleveland, OH 44195. Received September 12, 1989; revised and accepted October 31, 1989. © 1990 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/90/$3.50

MATERIALS A N D M E T H O D S Organisms Organisms tested r e p r e s e n t e d 1258 fresh and stock clinical isolates from patients at the Cleveland Clinic

46

C.C. Knapp et al.

Antimicrobial Susceptibility Testing

Foundation. In addition, 18 isogenic pairs of wild types and mutants of Gram-negative bacilli derepressed for Type I 13-1actamase, 12 stably derepressed mutants for Type 113-1actamase without wild type pairs, and four non-Type I hyperq3-1actamaseproducing strains of Enterobacteriaceae were kindly provided by Christine C. Sanders (Creighton University, Omaha, Nebraska).

Minimum inhibitory concentrations (MICs) were determined with an inoculum of approximately 5 x 10 s CFU/ml in cation-adjusted Mueller-Hinton broth by the broth microdilution method with controls as recommended by the National Committee for Clinical Laboratory Standards (1988).

Antimicrobial Agents

RESULTS

Cefoperazone and sulbactam were provided by Roerig Division of Pfizer Pharmaceuticals (New York, New York). Each antimicrobial powder was stored and reconstituted according to instructions provided by the manufacturer.

The MIC ranges and MICso and MICg0 values for cefoperazone alone and combined with sulbactam at two fixed concentrations and in a 2:1 ratio against clinical isolates from the Cleveland Clinic Foundation are listed in Table 1. The addition of sulbactam

TABLE 1.

Antimicrobial Activity of Cefoperazone, Alone and Combined with Sulbactam in Concentrations of 2 and 4 i~g/ml and in a 2:1 Ratio Against Clinical Isolates from the Cleveland Clinic Foundation MIC ~g/ml Cefoperazone! Sulbactam

Cefoperazone/ Sulbactam

Cefoperazone/

(2 lag/ml)

(4 gg/ml)

Sulbactam (2:1)

Cefoperazone No.

Organism

Tested

Range

50%

90%

84yt ~ 1-2

16 64

4 2 ~64

64

>64

4->64

64

>64

4->64

64

>64

4->64

32

64

41

64

2

8

E 1->64

2

16

E 1->64

2

8

~ I->64

2

8

Strept~x:uccus,

42

E0.5

E0.5

E0.5

~0.5

~0.5

E0.5

~0.5

[5-hemolytic Enterococcus Streptococcus pneumoniae

46 15

~64 E1

32 64

32

31 21 19 8 °fl 2 2

.

2b

67c 35 30 30

16

. . 5 0 7 0 12 6 . . . 2 3 2 2 1 4 . . . 15 2 13 8 14 24

8 . 0 0 0 . 1 2 1 . 3 3 11

4 .

2

~