DIAGN MICROBIOLINFECTDIS 1990;13:67-69

67

Activity of Cephalosporins Against Coagulase-Negative Staphylococci Nai-Xun Chin, Natalie M. Neu, and Harold C. Neu

Staphylococcus epidermidis has become an increasingly important pathogen as the cause of serious postoperative infection after heart and orthopedic surgery. We studied the susceptibilities of 80 blood, sternotomy, and hip isolates to vancomycin, cefazolin, cefuroxime, oxacillin, erythromycin, ciprofloxacin, and ofloxacin. The MICgo of methicillin-susceptible isolates was 41~g/ml for cefazolin and cefamandole, 81~g/ml for cefuroxime, and 41~g/ml for vancomycin. At 48 hr the MICgo rose to

32~,g/ml for cefazolin and >1281~g/ml for cefuroxime, and remained at 41~g/ml for cefamandole and vancomycin. The MIC~ of methicillin-resistant isolates at 48 hr was 16~,g/ml cefamandole, 64p,g/ml cefazolin, >1281~g/ml cefuroxime, and 4p,g/ml vancomycin. Ciprofloxacin and ofloxacin inhibited the majority of isolates at lp, g/ml, and vancomycin at 41~g/ml. The new peptolide, daptomycin, also inhibited S. epidermidis at ~lp, g/ml.

Staphylococcus epidermidis and other coagulase-negative staphylococci such as S. hemolyticus have assumed increasing importance in clinical infectious diseases as there is a continued and increased use of prosthetic material in major surgical procedures (Dickinson and Bisno, 1989a, 1989b). The primary organism causing both early and late postoperative infection after cardiac surgery or orthopedic surgery in which there has been hip replacement is S. epidermidis (Andrews et al., 1981; Calderwood et al., 1985). Coagulase-negative staphylococci also are an important cause of infection in patients with long indwelling intravenous (I.V.) lines such as Broviac and Hickman catheters. Characteristically prophylaxis of operative procedures on the heart and hip have been with a first generation cephalosporin. Originally cephalosporins such as cephalothin with short half-lives, 0.8 hr, were used, but in recent years cefazolin, which has a half-life of 2 hr, has been the agent of choice as it can be administered every 8 hr. We wished to determine the susceptibility of coa-

gulase-negative staphylococci to three cephalosporins routinely used as prophylactic agents at the time of surgery and compare this to vancomycin, a new lipopeptide, and to quinolones. Coagulase-negative staphylococci used in this study were isolates obtained from patients hospitalized at The Presbyterian Hospital in New York City. They had been identified by the API method and had been stored frozen. All of the isolates were from blood cultures, sternotomy wounds, or hip prosthesis infections and had been collected over a 4-yr period. Only a single isolate from a patient was used, and the isolates were considered clinically significant. Susceptibility tests were performed using an inoculum of 104 CFU applied to agar with a multipoint inoculator (NCCLS, 1988). Mueller-Hinton agar, pH 7.4, was supplemented with 3% NaCI. Incubation was at 35°C for 24 and 48 hr. MICs were determined at 48 hr to detect subpopulations that were resistant to the compounds. Susceptibility to oxacillin was determined initially for all of the isolates. Organisms with oxacillin MICs ~4~g/ml were considered resistant to methicillin. The results of this study for methicillin-(oxacillin)susceptible isolates are shown in Table 1. If an MIC of ~8~g/ml is considered clinically useful at 24 hr, all of the agents had MICg0s equal or less than this value. When the assays were re-read at 48 hr, the MICs had increased two-fold. The MIC90s at 24 hr were 4~g/ml for cefazolin and cefamandole, and 8~g/

From the Departments of Medicine (N-X.C., H.C.N.) and Pharmacology(H.C.N.), College of Physicians& Surgeons, Columbia University, New York, New York. Address reprint requests to: Dr. Harold C. Neu, Department of Medicine, 630 West 168 Street, New York, NY 10032. Received July 6, 1989; revised and accepted November 13, 1989. © 1990 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/90/$3.50

N.-X. Chin et al.

68

TABLE 1.

MIC Distributions of Cefazolin, C e f a m a n d o l e , Cefuroxime, a n d V a n c o m y c i n Against 40 Methicillin-Susceptible Strains of Staphylococcus epidermidis

Incubation

MIC (~g/ml) Time (hr)

Agent Cefazolin

24 48 24 48 24 48 24 48

Cefamandole Cefuroxime Vancomycin

>128

64

32

16

8

4

2

1

0.5

0.25

1 3

6

2 1

2 1 2 3 4 3

5 4 5 4 6 3 14 22

9 5 8 1 4 4 24 11

7 10 2 9 4 4 2 1

12 9 12 6 9 10

2 1 8 4 7 5

1 1

3 10

1

6

ml for cefuroxime and 4 ~,g/ml for v a n c o m y c i n . The MICg0s at 48 hr had increased to 32 ~,g/ml for cefazolin, >128 ~g/ml for cefuroxime, w h e r e a s the 48hr c e f a m a n d o l e MIC9~ r e m a i n e d at 4 ~g/ml as it did for vancomycin. Table 2 p r o v i d e s the results for the methicillinresistant isolates. At an MIC of ~ 8 ~g/ml cefazolin and c e f a m a n d o l e inhibited 90% of isolates as did vancomycin, but 27.8 bLg/m[ (geometric mean) for cefuroxime. The MICgo against the methicillin-resistant isolates w a s lowest for c e f a m a n d o l e , 8 ~g/ml at 24 hr a n d 16 ~.g/ml at 48 hr; w h e r e a s at 48 hr the M I C ~ was 64 ~g/ml for cefazolin a n d >128 ~.g/ml for cefuroxime. V a n c o m y c i n had MICg0 of 4 ~.g/ml at both 24 and 48 hr. It should be noted that nine of the 80 isolates had v a n c o m y c i n MICs of 8 ~g/ml. Table 3 s h o w s the c o m p a r a t i v e M I C ~ a n d MICgo for the cephalosporins, glycopeptides, peptolide, and two new quinolones. All of the isolates w e r e inhibited by 1 ~g/ml of d a p t o m y c i n , ciprofloxacin, a n d ofloxacin. Fifty percent of the methicillin-susceptible and 90% of the methicillin-resistant isolates w e r e resistant to e r y t h r o m y c i n . TABLE 2.

Cefazolin Cefamandole Cefuroxime Vancomycin

2 2 2

0.06

1

8 32 4 4 8 ~>128 4 8

1.5 2.7 0.8 1.! 1.5 3.5 2.5 3.5

We u n d e r t o o k this s t u d y b e c a u s e m o s t of o u r patients u n d e r g o i n g cardiac surgery or joint replacem e n t received cefazolin prophylaxis. In recent years s t e r n o t o m y w o u n d infection d u e to S. epidermidis is c o m m o n (Dickinsen a n d Bisno, 1989a). From this s t u d y one w o u l d question the use of cefazolin as a prophylactic a g e n t if c o a g u l a s e - n e g a t i v e staphylococci w e r e possible p a t h o g e n s to be p r e v e n t e d at the time of surgery in view of the high MICs of the methicillin-resistant isolates. In contrast, m o s t of the methicillin-susceptible isolates of S. epidermidis w o u l d be inhibited by achievable concentrations. We noted that 80% of hospital isolates, obtained after 3 days, are methicillin-resistant, w h e r e a s m o r e than 70% of c o m m u n i t y isolates are methicillin-susceptible. Cefuroxime in vitro a p p e a r s not satisfactory for prophylaxis of methicillin-resistant isolates. Excellent postoperative infection rates have been achieved with cefuroxime in cardiac s u r g e r y cases (Slama et al., 1986), but the length of time the patients had been hospitalized is not k n o w n . C e f a m a n d o l e has been u s e d as a prophylactic a g e n t for cardiac surgery

MIC Distributions of Cefazolin, C e f a m a n d o l e , Cefuroxime, a n d V a n c o m y c i n Against 40 Methicillin-Resistant Strains of Staphylococcus epidermidis

Incubation

Agent

0.12

Geometric Mean Value of MIC MICgo (~,g/ml)

MIC (~,g/ml) Time (hr) 24 48 24 48 24 48 24 48

>128 1 2

64

32

16

8

4

2

1

0.5

0.25

0.12

7 11

5 9

5 4 2 4

7 5 4 11 2 1

6

2 3 4

1

4 5 2

1 1 4 5 2 1

1

2 26 31

3 1

3

22 17 2 1 21 27

17 9

l 1 1 2 1

4 4

0.06

1 1

3128 3128

MIC~) 64 64 8 16 27.8 42.2 4 4

Geometric Mean Value of MIC (jxg/ml) 8 13.9 2.5 4.2

2.8 3.5

Notes

TABLE 3.

69

Comparative MICs of Cephalosporins and O t h e r Agents Against Coagulase-Negative Staphylococci Inhibitory Concentration (~g/ml) of:

MethicillinSusceptible S. epidermidis

Methicillin-Resistant S. epidermidis

Agent

50%

90%

50%

90%

Cefazolin Cefuroxime Cefamandole Vancomycin Teicoplanin Daptomycin Ofloxacin Ciprofloxacin Erythromycin

2 2 1 2 2 0.25 0.25 0.25 0.12

4 8 4 4 2 1 1 1 >32

8 > 128 4 2 2 0.5 0.25 0.25 >32

64 >128 8 4 4 0.5 1 1 >32

with excellent results (Kaiser et al., 1987; Parr and Aber, 1982; Myerowiz et al., 1977). Nonetheless, its short half-life, 0.7 hr, requires that larger doses and more frequent administration be used. Vancomycin administered at a dose of l g before surgery would provide peak serum levels of 20~g/ml with a halflife of 6 hr. For this reason we have elected to continue to use cefazolin as prophylaxis for patients admitted immediately before surgery, but we use v a n c o m y c i n as prophylaxis for patients w h o have been in the hospital or recently received antibiotics. W h e t h e r the new quinolones such as ciprofloxacin or ofloxacin would be suitable as prophylaxtic agents since their MIC90s were ~ l ~ g / m l , or w h e t h e r such use would result in an increase of MICs of

coagulase-negative staphylococcus is u n k n o w n . Daptomycin, a n e w peptolide, also s h o w e d excellent activity against both methicillin-susceptible and methicillin-resistant coagulase-negative staphylococci. The explanation for the discrepancy in MICs of cefazolin, cefamandole, and cefuroxime for S. epidermidis may be related to differences in beta-lactamase susceptibility as Kernodle et al. (1989) have s h o w n for S. aureus, or to binding to penicillin-binding proteins. We currently have f o u n d several different beta-lactamases in S. epidermidis (Gu and Neu, u n p u b l i s h e d data) and are in the process of purifying the enzymes.

REFERENCES Andrews HJ, Arden GP, Hart GM, Owen JW (1981) Deep infection after total hip replacement. J Bone Joint Surg [Br] 63:53-57. Calderwood SB, Swinski LA, Waternaux CM, Karchner AW, Buckley MJ (1985) Risk factors for the development of prosthetic valve endocarditis. Circulation 72:3137. Dickinson GM, Bisno AL (1989a) Infections associated with indwelling devices: concepts of pathogens: infections associated with intravascular devices. Antimicrob Agents Chemother 33:597-601. Dickinson GM, Bisno AL (1989b) Infections associated with indwelling devices: infections related to extravascular devices. ANtimicrob Agents Chemother 33:602-607. Kaiser AB, Petarcek MR, Lea JW, et al. (1987) Efficacy of cefazolin, cefamandole, and gentamicin as prophylactic agents in cardiac surgery: results of a prospective, randomized, double-blind trial in 1030 patients. Ann Surg 206:791-797.

Kernodle DS, Stratton CW, McMurray LN, Chipley JR, McGraw PA (1989) Differentiation of beta-lactamase variants of Staphylococcus aureus by substrate hydrolysis profiles. J Infect Dis 159:103-108. Myerowiz PD, Caswell K, Lindsay WG (1977) Antibiotic prophylaxis for open-heart surgery. J Thorac Cardiovasc Surg 73:625-629. National Committee for Clinical Laboratory Standards (1988) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. M7-T2. Villanova, PA: NCCLS. Parr GV, Aber RC (1982) Comparative efficacy and tolerance of cefamandole and cephalothin as prophylaxis for open-heart surgery: a randomized double-blind study. ] Cardiovasc Surg 23:305-308. Slama TG, Sklar SJ, Misinski J, Fess SW (1986) Randomized comparison of cefamandole, cefazolin, and cefuroxime prophylaxis in open-heart surgery. Antimicrob Agents Chemother 29:744-747.

Activity of cephalosporins against coagulase-negative staphylococci.

Staphylococcus epidermidis has become an increasingly important pathogen as the cause of serious postoperative infection after heart and orthopedic su...
229KB Sizes 0 Downloads 0 Views