prophylaxis in cardiac surgery. a controlled randomized comparison between cefazolin and cefuroxime

8/7/2019 Prophylaxis in cardiac surgery. A controlled randomized comparison between cefazolin and cefuroxime

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1995;9:325-329Eur J Cardiothorac SurgF Wellens, M Pirlet, R Larbuisson, F De Meireleire and P De Somer

and cefuroximeProphylaxis in cardiac surgery. A controlled randomized comparison between cefazolin

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Association for Cardio-Thoracic Surgery. Published by Elsevier. All rights reserved. Print ISSN: 1010-7940.Cardio-thoracic Surgery and the European Society of Thoracic Surgeons. Copyright 1995 by EuropeanThe European Journal of Cardio-thoracic Surgery is the official Journal of the European Association for

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Eur J Cardio-thorac Surg (1995) 9:325-329 - - European Journal ofCardiOthoracicSurgery Sprmger-Verlag 1995

Prophylaxis in cardiac surgeryA c o n t r o l l e d r a n d o m i z e d c o m p a r i s o n b e t w e e n c e f a z o l in a n d c e f u r o x i m eF . W e l l ens 2 , M . P i r l e t 2, R . L arb ui s so n a , F . D e M e i re l e i re 3 , P . D e Som er 11 Department of Cardiac Surgery, Onze Lleve Vrouwmekenh uis, Moorselbaan 164, 9300 Aalst, Belgium2 Department of Anesthesia, Centre Hospitalier Unlversitalre du Sart Tilman. Liege, Belgium3 D epartment of Infectious Diseases, Onze Liev e Vrouwziekenhuis, M oorselhaan 164, 9300 Aalst, Belgium

A b s t r a c t . I n a p r o s p e c t i v e r a n d o m i z e d t w o c e n t e r t r i a l, s h o r t - t e r m p r o p h y l a x i s w i t h c e f u r o x i m e ( C F X ) i n 1 8 9 p a -t i en t s w a s c o m p a r e d w i t h c e f a z o l i n ( C F Z ) i n 1 9 6 p a t i e n t s s u b m i t t e d t o e l e c t i v e c a r d i a c s u r g e r y . A t o ta l o f 3 g w a sa d m i n i s t e r e d o v e r 2 4 h in b o t h g r o u p s . O n e m a j o r a d v e r s e r e a c t i o n w i t h C F X w a s n o t e d . P a t i en t s w e r e p r o s p e c -t i v e l y s c r e e n e d b y i n f e c t i o u s d i s e a s e n u r s e s f o r s u r g i c a l w o u n d a n d s e c o n d a r y i n f e c t i o n s . S t e r n a l w o u n d i n f e c -t i o n s o c c u r r e d i n e i g h t p a t i e n ts t r e a t e d w i t h C F X a n d a l l w e r e m i n o r . O n e p a t i e n t f r o m t h i s g r o u p e v e n t u a l l y d i e do f i n f e c t i o u s c a u s e s . I n t h e C F Z - t r e a t e d p a t i e n t s t w o m a j o r a n d s i x m i n o r w o u n d i n f e c t i o n s o c c u r r e d r e q u i r i n ge x t e n s i v e d e b r i d e m e n t i n t w o . S e c o n d a r y i n f e c t i o n s o c c u r r e d l e s s f r e q u e n t l y i n th e C F X g r o u p ( 1 3 .2 p e r 1 0 0 ) t h a ni n t h e C F Z g r o u p ( 1 6 .8 p e r 1 0 0 ) w i t h t w o i n f e c t i o n - r e la t e d d e a t h s i n t h e C F X a n d o n e i n t h e C F Z g r o u p . T h e m o s tc o m m o n l y i d e n t if i ed o r g a n i s m s w e r e Staphylococcus aureus a n d a v a r i e ty o f g r a m - n e g a t i v e o r g a n i s m s . N o m a j o rd i f f e r e n c e s w e r e o b s e r v e d b e t w e e n t h e C F X a n d C F Z g r o u p s . S h o r t - t e r m a d m i n i s t r a t i o n o f 3 g C F Z o r C F X i nt h i s s tu d y c o u l d n o t d e m o n s t r a t e t h e a d v a n t a g e o f o n e o f t h e a n t ib i o t i c s u s e d o v e r t h e o t h e r i n t e r m s o f c li n i c a lo u t c o m e , i n c i d e n c e o r s i te o f i n f e c t i o n o r o r g a n i s m s i d e n t i f i e d . T h e 2 4 h a d m i n i s t r a t i o n o f 3 g C F Z o r C F X p r o -v i d e d s u b o p t i m a l p r o p h y l a x i s f o r w o u n d i n f e c t i o n o r s e c o n d a r y i n f e c t i o n s i n p a t i e n t s u n d e r g o i n g e l e c t i v e o p e nh e a r t s u r g e r y . [ E u r J C a r d i o - t h o r a c S u r g ( 1 9 9 5 ) 9 : 3 2 5 - 3 2 9 ]K e y w o r d s : C a r d i a c s u r g e r y - I n f e c t i o n - A n t i b i o t i c s - P r o p h y l a x i s - S t e r n u m

T h e p o s s i b l e l i f e - t h r e a t e n i n g c o n s e q u e n c e o f i n f e c t io n i np a t i e n t s u n d e r g o i n g c a r d i a c s u r g e r y j u s t i f i e s t h e p r o p h y -l a c t i c u s e o f a n t i b i o t i c s [ 1 , 3 , 7 , 1 0, 1 9 ]. T h e o r g a n i s m sc a u s i n g i n f e c t i o u s p r o b l e m s a f t e r c a r d i a c p r o c e d u r e s a r ee q u a l ly d i v i d e d b e t w e e n S t a p h y l o c o c c a l s p e c i e s a n d E n -t e r o b a c t e r i a c e a e , a l t h o u g h t h e p r o p o r t i o n o f e a c h v a r i e sc o n s i d e r a b l y f r o m s t u d y t o s t u d y. S e v e r a l a n t i b i o t i c s h a v eb e e n e v a l u a t e d f o r p r o p h y l a x i s a n d e s p e c i a l l y th e c e p h a -l o s p o r i n s a r e v e r y f r e q u e n t l y u s e d b e c a u s e o f t h e i r s p e c -t r u m o f a c t i v i t y , p h a r m a c o k i n e t i c p r o f i l e a n d t h e l a c k o fm a j o r t o x i c it y . C e f a z o l i n ( C F Z ) , o n e o f t h e f ir s t c e p h a l o s -p o r i n s a v a i l a b le , h a s b e e n a p o p u l a r c h o i c e f o r p r o p h y l a c -t i c t h e r a p y a m o n g c a r d i o v a s c u l a r s u r g e o n s [ l 7 ] . H o w e v e r ,t h e i n c r e a si n g p r e v a l e n c e o f r e s is t a n c e o f g r a m - n e g a t i v eb a c i l l i h a s e n c o u r a g e d i n v e s t i g a t o r s t o e v a l u a t e s e c o n dg e n e r a t io n c e p h a l o s p o r i n s s u c h a s c e f u r o x i m e ( C F X ) [ 2.5 , 8 , 1 1 ] . S e v e r a l a u t h o r s [ 2 , 8 , 1 3 , 1 5 , 1 7 ] h a v e s u g g e s t e db e t t e r e f fi c a c y in p r e v e n t i n g p o s t o p e r a t i v e w o u n d i n f e c -t io n w i t h C F X a n d c e f a m a n d o l e t h a n w i t h C F Z i n c a r d io -Received for publication: March 2. 1994Accepted for publication: January 10. 1995Correspondence to: E Wellens. M. D.

v a s c u l a r s u r g e r y . W i t h t h e e x c e p t i o n o f t h e r e c e n t s t u d y o fD o e b b e l i n g a n d c o - w o r k e r s [ 5 ] , f e w c o m p a r i s o n s h a v eb e e n m a d e b e t w e e n t h e p r o p h y l a c t ic u s e o f C F X a n d C F Z .

T h e c h a n g i n g p a t t e r n s o f t h e p a t i e n t p o p u l a t i o n i n t w ot e r t i a ry r e f e r r a l c e n t e r s ( a s i n o t h e r o p e n h e a r t s u r g e r y p r o -g r a m s [ 4 ] ) , t h e e x t e n s i v e u s e o f o n e o r b o t h i n t e r n a l t h o -r a c i c a r t e r i e s i n r e c e n t y e a r s w i t h i n c r e a s e d m o r b i d i t y o fs t e r n a l i n f e c t i o n s [ 1 5 ] a n d t h e c o n t r o v e r s i a l r e s u l t s w i t hv a r i o u s a n t i b i o t i c s i n t h e l i t e r a t u r e w e r e t h e r e a s o n s f o rs t a r t i n g a p r o s p e c t i v e r a n d o m i z e d t r i a l c o m p a r i n g t h e e f -f i c a c y o f C F X a n d C F Z i n p r e v e n ti n g p o s t o p e r a t i v e i n f e c -t i o n s i n o p e n h e a r t s u r g e r y.

P a t i e n t s a n d m e t h o d sPatient selectionPatients over 18 years of age admitted for elective coronary arterybypass grafting, cardiac valve replacement or reconstruction andsimple congenital lntracar&ac repair were considered to receiveCFX o r CFZ antibiotic prophylaxis in this randomized trial. All pro-cedures were performed at the Onze Lieve Vrouw Ziekenhuis Aalstand at the University Hospital of Liege Belgium over a period of

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3261 year. To be included in the study the patients could have neitherhypersensivity to cephalosporins, nor fever of more than 38 C. Pre-vious antibiotic treatment within 3 days before admission, hospitaladmission exceeding 36 h before operation and immunocomprom-ised patients (less than 1000 polymorphonuclear neutrophils) wereabsolute exclusion criteria.

Study designA non-blindrandomized comparison of 24 h prophylaxis with CFXversus CFZ was carried out in two groups of 200 evaluable patients .Four hundred patients had to be included in the study in order to al-low a 50% reduction of the infecti on rate when starting with the hy-pothesis of 14% infection rate and a study power of 80%. A seriesof scaled numbered envelopes, containing the treatment allocationwas used. The envelopes were opened in numerical order, one foreach patient after i nclusion in the study. Ran domization was carriedout in advance for the whole group by a computer program for se-ries of 200 patients.

Study medicationBoth CFX and CFZ were administered in bolus during the first op-erative day. Cefuroxime was given intravenously at a total dosageof 3 g divided in two injections of 1.5 g. The first injection of CFXwas admin istered at the induction of anesthesia. The second dosagewas given 12 h later on the intensive care unit. Cefazolin was ad-minis tered intravenously at a total dosage of 3 g divided in three in-jections of 1 g. The first injection was administered at the inductionof anesthesia. The second and third injections of 1 g CFZ were giv-en, respectively, 8 and 16 h later.

Clinical evaluation a nd surveillancePatients had a full clinical examination the day before operation andclinical assessment was carried out daily during the hospitalizationperiod by one of the cardiovascular (CV) staff surgeons, and separ-ately by the infec tions disease room nurses (RN) assigned to thestudy. An individ ual study book was used for each patient and datawere entered on a day-to-day basis. Skin preparation was carried outwith povidone iodine the evening before operation and with iodinesolution intraoperatively. After hospital discharge patients were re-viewed at the outpatient clinic by the staff CV surgeon and RN re-sponsible for the study between 4 to 6 weeks postoperatively, or ear-her in case of i nfection problem.Rectal temperature was measured twice daily during hospitaliza-tion. A safety screen covering hematology (red blood cells, haemog-lobin , haematocrit, platelet count, prothrombin time and differentialwhite cell count and sedimentation rates), biochemistry (liver func-tion, blood urea nitrogen, serum creatinine and clearance) and urineanalysis (PH, density, biochemistry and microscopy and culture),was performed within 24 h before the operation, between 24and 48 h postoperatively and on the day of follow-up when ab-normal values which could be antibiotic related were noticedafter the second postoperative day. Creactive protein was not mon-itored. Bacteriologic assessment was carried out on appropriatesamples collected for culture and sensitiv ity when infec tion was sus-pected.Disc sensi tivity of the isolates was tested agmnst CFZ and CFXand a standard range of antibiotics including ampicillin, cephalotm,piperacillin, gentamycl n and cefotaxlme. All adverse even ts afteradmini stration of the antibiot ic were registered,

Criteria fo r diagnosing infectionIf, after 48 h postoperatively, two consecutive rectal t emperaturereadings were more than 38.0 C infect ion was suspected. Wound

infection referred to the presence of pus in the wound and seventyof wound infection was characterized as follows:grade 1 : disturbed wound healinggrade 2 : redness


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32 7Tab le 1. Baseline and operative characteristics and hospital stay intwo groups treated wxth esther CFX or CFZ

Cefuroxlme Cefazolin(N= 189) (N= 196)Ag e (years) 60.7 _+ 9.9 60.4 _+ 9.0Weight (kg) 72.5 + 12 74.0 + 11.7Heig ht (era) 168.2 + 8.4 169.2 + 8.2Tem perature 36.2 _+ 0.3 36.3 _+ 0.3before operation (C)Duration of operation (rain) 220.4 + 51.2 229.5 + 55.3Blood loss (cc) 901.5 + 640.8 900.8 _ 492.3Hospital stay (days) 13.4 + 4.9 13.6 + 5.2Operative indication (%, no in brackets)- CAB G 36.8% (142) 39.5% (154)-V alv epr oce dur e 9 .6% (37) 7 .5% (29)- C A B G + v a l v e 1 8 % ( 7) 2 .8 % ( 1 1 )- Congenital 0.8% (3) 0.5% (2)Mean values + standard deviation

Table 2. Early postoperat ive infectionsInfection site CFX group(n = 189) CFZ group Total( n = 1 9 6 ) ( n = 38 5 )

No. Death No. Death No.Sternal woundmajor 0 1minor 5 1 2Leg wound 1 1Pulmonary infection 9 14Urina ry tract infection 5 7Septicemia 4 1 8Catheter sepsis 3 1OtherTotal infections 27 34 61No. infected patients 20 2 28 1 48(10.6%) (14.2%) (12.5%)

22312124

C F X a t t h e t i m e o f i n d u c t i o n o f a n e s t h e s i a . F r o m t h e4 0 1 p a t i e n t s r e c r u i t e d f o r t h i s s t u d y 1 1 ( 2 . 7 % ) p a t i e n t sd i e d , 5 i n t h e C F Z g r o u p a n d 6 i n t h e C F X g r o u p . I n t h eC F X g r o u p t h r e e p a t i e n t s d i e d b e c a u s e o f i n f e c ti o n , i n t h eC F Z g r o u p o n e p a t i e n t d i e d a s a r e s u lt o f p n e u m o n i a ( T a -b l e 2 ) . T h e o t h e r d e a t h s w e r e n o t r e l a t e d t o a n y in f e c t i o n s ;f i v e o f t h e m w e r e e x c l u d e d f r o m t h e f u r t h e r t r i a l a s t h e yd i e d w i t h i n 3 d a y s a f t e r th e o p e r a t i o n f r o m n o n - i n f e c t i o u sc a u s e s .

E a r l y i n f e c t i o n , i .e . w i t h i n 2 w e e k s p o s t o p e r a t i v e l y , o c -c u r r e d i n 4 8 p a t ie n t s ( T a b l e 2 ). T w e l v e p a t i e n t s h a d t w oo r m o r e i n f e c t i o n s i t e s , o f w h o m 5 p r e s e n t e d w i t h i d e n t i -c a l g e r m s a t t h e i r m u l t i p l e i n f e c t i o u s s i te s . A d e l a y i n h o s -p i t a l d i s c h a r g e w a s n o t i c e d i n 2 4 p a t i e n t s ( 5 0 % ) .

I n t h e CFX g r o u p 2 7 i n f e c t i o n s o c c u r r e d i n 2 0 p a t i e n t s( 1 0 . 6 % ) . F i f t e e n p a t i e n t s h a d t o b e t r e a t e d w i t h a n t i b i o -t i cs . T w o d e a t h s w e r e d i r e c t l y i n f e c t io n - r e l a t e d . T e n o t h e rp a t i e n t s h a d a d e l a y i n h o s p i t a l d i s c h a r g e . N o n e o f t h e C F Xp a t i e n t s d e v e l o p e d a m a j o r s t e r n a l w o u n d i n f e c t i o n . O n eo f t h e f i v e p a t i e n t s w i t h m i n o r s t e r n a l w o u n d i n f e c t i o n sa l s o d e v e l o p e d p u l m o n a r y a n d u r i n a r y t r ac t i n f ec t i o n a n d

T a b l e 3 . Late infectionsNum ber of pat ients with CFX group CFZ groupproblems at follow-upTotal number 18 22Related to the operation 9 13Reqmring antibiotics 9 9Related to the operation 6 9and requiring antibiotics

e v e n t u a l l y d i e d f r o m m u l t i o r g a n f a i l u r e . O n e l e g w o u n di n f e c t i o n b u t 2 2 s e c o n d a r y i n f e c t i o n s w e r e r e g i s t e r e d i nt h e C F X g r o u p . O n e p a t i e n t d i e d f r o m s e p s i s c a u s e d b y a ni n t r a - a b d o m i n a l a b s c e ss .

I n t h e C F Z g r o u p 3 4 i n f e c t i o n s w e r e n o t e d i n 2 8 p a -t i e n ts ( 1 4 . 2 % o f t h e g r o u p ) . T w e n t y - t w o p a t i e n t s n e e d e da n t i b i o t i c t r e a t m e n t . O n e p a t i e n t d e v e l o p e d a m a j o r s t e r -n a l w o u n d i n f e c t i o n a n d t w o o t h e r s a m i n o r s t e r n a l w o u n dp r o b l e m . T h i r t y s e c o n d a r y i n f e c t i o n s w e r e n o t e d , w i t h o n ed e a t h i n a p a t i e n t w i t h a p u l m o n a r y i n f e c t i o n . F o r 1 3 o t h e rp a t i e n t s a d e l a y i n h o s p i t a l d i s c h a r g e w a s d i r e c t l y r e l a t e dt o t h e i n f e c t i o n .

S i g n i fi c a n t d i f f e re n c e s c o u l d n o t b e c o n c l u d e d b e t w e e nt h e t w o t r e a t m e n t g r o u p s f o r a n y o f t h e t y p e s o f i n f e c t io n s( F i s h e r t e s t o r c h i - s q u a r e d t e s t) . A n o t h e r e v a l u a t i o n o f e f-f i c a c y w a s c a r r i e d o u t b y c o m p a r i n g t h e a v e r a g e h o s p i ta ls t a y in t h e t w o t r e a t m e n t g r o u p s . T h e d u r a t i o n o f th e p o s t -o p e r a t i v e p e r i o d , i . e . d a y s b e t w e e n d a y o f o p e r a t i o n a n dd a y o f d i s c h a r g e , w a s 1 1 . 5 3 + 5 . 0 5 d a y s i n t h e C F X g r o u p( r a n g e : 2 - 4 9 d a y s ) a n d 1 1 . 6 6 + 5 . 3 2 d a y s in th e C F Z g r o u p( r a n g e : 7 - 4 7 d a y s ) . B o t h t h e t - t e s t a n d th e M a n n - W h i t n e yt e s t y i e l d e d n o n - s i g n i f i c a n t d i f f e r e n c e s b e t w e e n t h e t w ot r e a t m e n t g r o u p s. A n o t h e r m e a n s t o c o n t r o l e f f i c a c y w a st h e a n a l y si s o f t h e e v o l u t io n o f b o d y t e m p e r a t u r e. C o m -p a r i s o n o f t h e a c t ua l o r m a x i m a l t e m p e r a t u r e s y i e l d e d n o n -s i g n i f i c a n t r e s u l t s ( t - t e s t a n d M a n n - W h i t n e y t e s t ) .

A f t e r d i s c h a r g e 4 0 p a t i e n t s h a d a n i n f e c t i o u s p r o b l e m ,i n 2 2 i t w a s o p e r a t i o n - r e l a t e d ( T a b l e 3 ) . S i x p a t i e n ts f r o mt h e C F X g r o u p a n d n i n e p a t ie n t s f r o m t h e C F Z g r o u p r e -q u i r e d a n t i b i o t i cs . L a t e s t e r n a l w o u n d i n f e c t i o n s o c c u r r e di n t h r e e p a t i e n t s i n t h e C F X g r o u p a n d i n f i v e i n t h e C F Zg r o u p , o n e o f t h e m b e i n g c l a s s i f i e d a s m a j o r . S e c o n d a r yi n f e c t i o n s o c c u r r e d o n f o u r o c c a s i o n s i n t h e C F X g r o u pa n d o n 2 i n t h e C F Z g r o u p . L e g w o u n d i n f e c t i o n s o c c u r r e di n s i x p a t i e n t s i n t h e C F Z - t r e a t e d g r o u p a n d i n t w o i n t h eC F X g r o u p ( T a b l e 4 ).

T h e d i s t r i b u t i o n o f b a c t e r i a l s p e c i e s r e s p o n s i b l e f o r th ee a r l y o n s e t i n f e c t i o n s i s o u t l i n e d i n T a b l e 5 . I n t h e C F Xg r o u p 3 0 , a n d i n t h e C F Z g r o u p 3 3 p o s i t i v e c u l t u r e s w e r er e g i s t e r e d . T h e r e w a s a s i m i l a r i t y n o t e d f o r g r a m - p o s i t i v ec o c c i a s w e l l a s f o r g r a m - n e g a t i v e b a c i l li .I n o r d e r t o i n v e s t i g a t e w h e t h e r t h e v a r i a b l e a g e , w e i g h ta n d d u r a t i o n o f o p e r a t io n , b l o o d l o s s a n d h o s p i t a l s t a y w e r er e l a t e d t o t h e o c c u r r e n c e o f a p o s t - s u r g i c a l i n f e c t i o n , t h r e e -w a y A N O V A S w e r e c a r r i e d o u t . T h i s a n a l y s i s f a i l e d t od e m o n s t r a t e a n y r e l a t i o n b e t w e e n t h e t e s t e d p a r a m e t e r sa n d t h e o c c u r r e n c e o f i n f e c ti o n . O n t h e o t h e r h a n d , t h e r ew a s a h i g h l y s i g n i f i c a n t r e l a t i o n s h i p b e t w e e n t h e o c c u r -r e n c e o f a p o s t o p e r a t i v e i n f e c t io n a n d a p r o l o n g e d h o s p i -t a l s t a y i n t h i s s u b s e t o f p a t i e n t s .



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32 8T a bl e 4 . Late infectionsInfectio n site Cefuroxime (n = 183 ) Cefazolin (n=191)+ AB + ABSternal wound: majo r 0 0 1 1minor 3 0 4 2Leg wound 2 2 6 4Pulmonary tract 2 2 0 0Urinary tract 2 2 2 2Other 0 0 0 0Total num ber of patients 9 6 13 9(4.9%) (6.8%)AB, antlbiotm treatmentT a bl e 5. Organisms responsible for infection

Cefnroxlme CefazolinG r a m +S ta p h y lo co ccu ~ a u reu s 4 5S t a p h y l o c o c c u s s z m u l a n s 1 0S ta p h y lo co ccu s ep id ermid t s 3 4S t r e p t o c o c cu s p n e u m o n i a e 0 2S t rep to co cc u s h a emo l , g r C 1 0S t r e p t o c o cc u s f a e c a l i s 1 3C o r y n e b a c t e r i u m species 1 -Anaerobic Streptococcus 1 -

12 14G r a m -

E sch e r t ch ia co l t 2 3K leb s t e l la o xy to ca 1 2K l e b s i e l la p n e u m o m a e 4 1H a e m o p h i l u s m f l u e n z a e 1 4E n t e r o b a c t e r c l o a c a e 4 2S e r r a t t a m a r c e s c e n s 4 1P s e u d o m o n a s a e r u g m o s a 0 4P r o t e u s m i r a b i h s 0 2Salmonella 1 0Acinetobacter 1

18 19Total 30 33

D i s c u s s i o n

T h i s s t u d y w a s u n d e r t a k e n t o t e s t t h e p o s s i b l e a d v e ,n t a g eo f C F X o v e r C F Z i n th e p r e v e n t i o n o f p o s t o p e r a ti v e w o u n da n d s e c o n d a r y i n f e c t i o n s a f t e r o p e n h e a r t s u r g e r y .

T h e s t u d y o f S l a m a a n d c o - w o r k e r s ( 1 7 ) w a s a p r o s -p e c t i v e r a n d o m i z e d s t u d y c o m p a r i n g c e f a m a n d o l e , C F Xa n d C F Z a s a n t ib i o t i c p r o p h y l a x e s i n 3 0 0 p a t i e n t s o v e r4 8 h . T h e r e s u l t s w e r e n o t f a v o r a b l e f o r i n t r a v e n o u s ( I V )C F Z , w i t h t h e h i g h e s t r a t e i n t o t a l a n d w o u n d i n f e c t i o n s .C e f a z o l i n w a s u s e d a s t h e s t a n d a r d p r o p h y l a x i s i n t h e t w oc a r d i a c i n s t i t u t i o n s i n v o l v e d i n t h i s s t u d y . T h e r a p i dc h a n g e i n p a t i e n t d e m o g r a p h i c s w i t h o l d e r p a ti e n ts , m o r ee m e r g e n c y o p e r a t i o n s a n d t h e e x t e n s i v e u s e o f t h e i n t r a -t h o r a c i c a r t e r y o v e r t h e l a s t y e a r s w e r e a l l r e a s o n s t o e x -p e c t m o r e i n f e c t i o n s , t o g e t h e r w i t h a n i n c r e a s e i n e a r l ym o r b i d i t y a n d m o r t a l i ty . P e t e r s o n a n d c o - w o r k e r s [ 1 6 ] a n dG e r o u l a n o s a n d c o - w o r k e r s [ 9 ] s t a t e d t h a t C F X w a s a s e f -f e c t i v e a s c e f a m a n d o l e i n o p e n h e a r t s u r g e r y . I n a d d i t i o nC F X w a s l e s s c o s t l y a n d h a d a l e s s f r e q u e n t d o s a g e . I t

t h e r e f o r e s e e m e d r e a s o n a b l e t o c o m p a r e C F X t o th e c u r -r e n t l y u s e d C F Z a n t i b i o t i c p r o p h y l a x i s . F r o m t h e r e s u l t so b t a i n e d f r o m t h is s e l e c t i v e s t u d y p o p u l a t i o n w e c o u l d n o td e m o n s t r a t e t h e a d v a n t a g e o f e i th e r o f th e a n t i b i o t i c s u s e d .

S t e r n a l w o u n d i n f e c t i o n s o c c u r r e d i n 1 6 p a t i e n t s ; e i g h to f t h e m i n t h e f i r st 2 w e e k s a f t e r t h e o p e r a t i o n ( C F X : f i v ea n d C F Z t h r e e ) a n d e i g h t i n t h e l a te p h a s e ( C F X t h r e e a n dC F Z f i ve ) . H o w e v e r t h e o n l y t w o m a j o r s t e r na l i n f e c ti o n so c c u r r e d i n t h e C F Z g r o u p . B o t h p a t i e n t s n e e d e d e x t e n -s i v e d e b r i d e m e n t a n d e v e n t u a l l y h e a l e d . O n l y o n e p a t i e n tw i t h a m i n o r w o u n d i n f e c t i o n f r o m t h e C F X g r o u p d i e df r o m i n f e c t i o u s p r o b l e m s a s h e p r e s e n t e d s e v e r a l i n f e c -t io u s s i te s w i t h th e s a m e g e r m s a n d s u c c u m b e d f r o m m u l -t i o r g an f a i lu r e . L e g w o u n d c o m p l i c a t i o n s w e r e a l l m i n o ra n d m o s t w e r e s e e n a t t h e f i r s t o u t p a t i e n t c l i n i c c o n t r o l .H o w e v e r , s i x o u t o f e i g h t p a t i e n t s h a d r e c e i v e d a n t i b i o t i ct r e a t m e n t f r o m t h e i r f a m i l y p h y s i c ia n ; t h e s a m e o b s e r v a -t i o n w a s a l s o m a d e b y M i e d z i n s k i [ 1 5 ] .

T h i s t o t a l o f 2 6 s u r g i c a l in f e c t i o n s ( 1 5 i n t h e C F Z g r o u pa n d 1 1 i n th e C F X g r o u p ) r e p r e s e n t s a 6 . 7 % i n f e c t i o n r a t ef o r t h e e n t i r e s t u d y p o p u l a t i o n . F a r r i n g t o n [ 6 ] a n d W e l l s[ 1 8 ] r e p o r t e d a h i g h e r i n f e c t i o n r a t e a n d S l a m a [ 1 7 ] a lo w e rt o t a l i n f e c t i o n r a t e t h a n o u r r e s u l t s . T h e r e s u l t s o f t h e r e -c e n t r e p o r t b y D o e b b e l i n g a n d c o - w o r k e r s [ 5 ] w h o p e r -f o r m e d a p r o s p e c t i v e d o u b l e -b l i n d c o m p a r i s o n o f C F Z a n dC F X w e r e n e a r l y i d e n t i c a l to o u r s . I n t h e ir s t u d y D o e b b e l -i n g a n d c o - w o r k e r s [ 1 5 ] f o u n d t h a t C F Z w a s m u c h m o r ee f f i c i e n t i n p r e v e n t i n g s t e r n a l w o u n d i n f e c t i o n s t h a n C F X .I t i s i m p o r t a n t t o n o t i c e , h o w e v e r , t h a t t h e t w o p a t i e n t sw h o n e e d e d s u r g i c a l i n t e r v e n t i o n f o r s t e r n a l w o u n d i n f e c -t i o n i n o u r s t u d y w e r e b o t h f r o m t h e C F Z g r o u p .

A l t h o u g h t h e p a t i e n t s e l e c t i o n a n d t h e d i a g n o s i s o f i n -f e c t i o n i n o u r s tu d y a n d t h a t o f D o e b b e l i n g w e r e v e r y s i m -i la r , t h e r e a r e s o m e i m p o r t a n t d i f f e r e n c e s b e t w e e n t h e t w os t u d i e s i n t e r m s o f t h e n u m b e r o f p a t i e n t s , t h e f a c t th a t o u rs t u d y w a s a n o p e n s t u d y a n d , m a i n l y , i n t h e d u r a t i o n o fa n t i b i o t i c t r e a t m e n t : a s w e o n l y a d m i n i s t e r e d a n t i b i o t i cp r o p h y l a x i s f o r 2 4 h w h i l e t h e y g a v e i t f o r 4 8 h . A p p a r -e n t l y t h i s d i d n o t i n c r e a s e t h e n u m b e r o f s u r g i c a l i n f e c -t i o n s c o m p a r e d t o th e s e r i e s o f D o e b b e l i n g e t a l . [ 5] . T h i ss h o r t a n t i b io t i c c o u r s e d i d n o t e v e n i n f l u e n c e t h e i n c i d e n c eo f n o s o c o m i a l i n f e c t i o n s w h e n c o m p a r i n g t h e t w o s t u d ie so r o t h e r s [ 1 1 , 1 2 ] . I n D o e b b e l i n g ' s s t u d y n o s o c o m i a l i n -f e c t i o n s a c c o u n t e d f o r 1 6 .3 a n d 1 9 . 3 % i n t h e C F Z a n d C F Xg r o u p s , r e s p e c t i v e l y , w h i l e i n o u r s tu d y w e f o u n d 1 6 .3 a n d1 3 . 7 % , r e s p e c t i v e l y .I n o u r s t u d y i t i s i m p o r t a n t t o n o t i c e t h a t th i s s h o r t - c o u r s ea n t i b i o ti c t r e a t m e n t w a s i n s u f f i c ie n t t o p r o t e c t a n u m b e r o fp a t i e n t s f r o m m u l t i p l e i n f e c t io n s i t e s, w h i c h m e a n s a t o t a lf a i l u r e o f th e a n t i b i o t ic c o v e r a g e . I n d e e d i n t h e e a r l y p o s t -o p e r a t i v e i n f e c t i o n s ( T a b l e 2 ) w e n o t i c e d t h a t 2 8 i n f e c t i o n so c c u r r e d i n o n l y 2 0 p a t i e n t s i n t h e C F X g r o u p a n d 3 4 i n -f e c t i o n s i n o n l y 2 4 p a t i e n t s i n th e C F Z g r o u p . F i v e p a t i e n t sp r e s e n t e d t h e s a m e m i c r o - o r g a n i s m i n w o u n d a n d b l o o dc u l t u r e s s u g g e s t i n g t h a t e a r l y w o u n d i n f e c t i o n c a u s e d s e c -o n d a r y s e p t i c e m i a . N o c a s e o f n a t i v e o r p r o s t h e t i c e n d o -c a r d i ti s w a s o b s e r v e d i n t h e e n t i re s t u d y p o p u l a t i o n .

S u r g i c a l w o u n d a n d n o s o c o m i a l i n f e c t i o n s h a v e b e e ns t u d i e d i n m o s t s t u d i e s o n a n t i b i o t i c p r o p h y l a x i s . H o w -e v e r t h e e f f i c a c y o f a n i n d i v i d u a l a n t i b i o t i c o n e a c h t y p eo f i n f e c t i o n s h o u l d b e s t u d i e d s e p a r a t e l y a s p a t i e n t - r e l a t e d



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329factors are probably more important in a subset of secon-dary infections. Due to the discrepancy in patient selec-tion, study design, duration of antibiotic administrationand diagnosis of infection, comparis on of our study resultswith those of Gentry [8], Slama [17] and Geroulanos [9],is more hazardous and of less value.Another observation f rom our study was the prevalenceof gram-negative organisms present in the surgical woundas well as in the nosocomial infections. Often a combina-tion was found of both gram-positive and -negative organ-isms. Indeed, the frequency of enterobacteriacae also sug-gests that nonantibiotic measures have to be intensified[14]. It leads us to the question of whether we have to usewider spectrum antibiotics in the early postoperative phaseor if we have to limit ourselves to an adequate gram- pos-itive coverage in order to avoid a rapid change in thepatient's bacteriologic household.

Even if one keeps to the choice of first or second gen-eration cephalosporins we have to take into account the lo-cal bacteriologic profile of every institution. Recently wecould observe an important increase in isolates of Staph-yloccocus epidermidis resistant to methicillin. C ontinuouscollaboration with the Infectious Disease Department ismandatory to adapt antibiotic prophylaxis to the changinginstitutional bacteriologic profile.

In view of the increasing demands put on the cardiacsurgical teams and the devastating consequences of surgi-cal sternal and/or mediastinal infections, one has to focusnot only on efficient antibiotic perioperative covera ge buteven more on the classical rules of surgical asepsis andmeticulous surgical techniques as recently advocated byLoop and co-workers [14]. More attention must also begiven to ICU infectious surveillance and fast retrieval ofindwelling catheters.

Economi c considerations do not play an important rolein the choice between C FX and CFZ as the price per 24 hdosage in nearly identical. Due to the short administrationof both antibiotics, any difference in administering costswas negligible in our study. In contrast, delay in hospitaldischarge due to infection was obvious in both groups. Theeconomic impact of prolonged hospitalization is muchmore important than the small variation of cost due to dos-age, short- or medium-te rm use or administrative costs.

In conclusion, this randomized controlled study couldnot demonstrate the advantage of one of the antibioticsused over the other in open heart surgery prophylaxis. Theywere both good in preventing major wound infections,while the incidence of minor wound and secondary infec-tions was high. In view of these results we have to face thefact that none of the cephalosporins used can provide thecardiac surgeon with a highly effective protection againstall surgical or secondary infections. Further research andevaluation of newer antibiotics together with more strin-gent local and surgical technical measures will be the onlyway to reduce the devastating conse quences of infectionsin open heart surgery.Acknowledgements.The authors would like to thank L. Kaufmanand M.R Derde (Biostatistics, FASC, Free University Brussels) forthe statistical analysis. The study was supported by a grant fromGLAXO, Belgium.

Re f e r e n c e s1. Beam TR (1987) Perioperative prevention of infection in car-diac surgery. Antibiot Chemother (Washington, D.C.) 33:114-1392. Conklin CM, Gray RJ, Neilson D, Wong P, Tomita DK, MatloffJM (1988) Determinants of wound infecnon incidence after iso-lated coronary artery bypass surgery in patients randomized to

receive prophylactic cefuroxime or cefazolin. Ann Thorac Surg46:172-1773. Conte JE, Cohen SN, Roe BB, Elashoff RM (1972) Antibioticprophylaxis and cardiac surgery; a prospective double-blindcomparison of single dose versus multiple dose regimens. AnnIntern Med 76:943-9494. Disch DL, O'Connor GT, Birkmeyer JD, Olmstead EM, LevyDG, Plume SK (1994) Changes in patients undergoing coronaryartery bypass grafting: 1987-1990. Ann Thorac Surg 57:416-4235. Doebbeling BN, Phaller MA, Kuhns KR, Massanari RM, Be-rendt DM, Wenzel RP (1990) A randomized controlled compar-ison of cefazolin and cefuroxime. J Thorac Cardiovasc Surg99:981-9896. Farrington M, Webster M, Fenn A, Phillips I (1985) Study ofcardiothoraclc wound infection at St. Thomas' hospital. Br JSurg 72:759-7627. Fong IW, Baker CB, Mc Kee DC (1979) The value of prophy-lactic antibiotics in aorto-coronary bypass operations: a double-blind randomized trial. J Thorac Cardiovasc Surg 78:908-9138. Gentry LO, Zeluff BJ, Cooley DA (1988) Antibiotic prophylax-is in open-heart surgery : a comparison of cefamandole, cefu-roxime and cefazolin. Ann Thorac Surg 46:167-1719. Geroulanos S, Oxelbark S, Donfrled B, Becker F, Turina M(1987) Antlmicrobial prophylaxis in cardiovascular surgery.Thorac Cardiovasc Surg 35:199-20310. Goodman JS, Schaffner W, Collins HA, Battersy EJ, KoeningMG (1968) Clinical study including examination of antimicro-blal prophylaxis. N Engl J Med 278:117-12311. Hasselgren PO, Ivarsson B, Risberg B, Seeman T (1984) Effectsof prophylactic antibiotics in vascular surgery. Ann Surg200:86-9212. Hillis DJ, Rosenfeldt FL, Spicer WJ, Stirling GR (1983) Anti-biotic prophylaxis for coronary bypass grafting. J Thorac Car-diovasc Surg 86:217-22113. Kreter B, Woods M (1990) Meta-analysis of antibiotic prophy-laxis trials for cardiothoracic surgery. Thirty years of clinicaltrials. Temple University Health Sciences Center, Philadelphia,PA and St. Luke's Hospital of Kansas City, Kansas City, MO.Draft 1,2.14. Loop FD, Lyttle BW, Cosgrove DM, Mahfood S, McHenry MC,Goormastic M, Stewart RW, Golding LAR. Taylor PC (1990)Sternal wound complications after isolated coronary artery by-pass grafting: early and late mortality, morbidity and cost ofcare. Ann Thorac Surg 49(2):179-18715. Mledzinski LJ, Callaghan JC, Fanning EA, Gelfand ET,Goldsand G, Modry D, Penkoske P. Preiksaitis J, Sheehan G,Sterns L, Taylor GD. Tyrell DLJ (1990) Antimicrobial prophylaxis for open heart operations. Ann Thorac Surg 50:800-80716. Peterson CD, Lake KD, Arom KV, Love KR (1987) Antibioticprophylaxis in open heart surgery patients: comparison of cef-amandole and cefuroxime. Drug Intelligence and Clinical Phar-macy 21 (9):728-73217. Slama TG, Sklar SJ, Misxnski J, Fess SW (1986) Randomizedcomparison of cefamandole, cefazolin and cefuroxime prophy-laxis in open heart surgery. Antimicrob. Agents Chemother.29:744-74718. Wells FC, Newsom SWB, Rowlands C (1983) Wound infectionin cardiothoracic surgery. Lancet I: 1209-121019. Wilson APR, Treasure T, Sturridge MI, Grtmeberg RN (1986)Antibiotic prophylaxis in cardiothoracic surgery in the UnitedKingdom: current practice. Thorax 41:396-400



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1995;9:325-329Eur J Cardiothorac SurgF Wellens, M Pirlet, R Larbuisson, F De Meireleire and P De Somer

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