Ceftizoxime Level in the Myocardium (Right Atrial Muscle and Mitral Papillary Muscle) during Open Heart Surgery

Minoru KOBAYASHI, Masahiko WASHIO, Hoshi EISHIN, Takao SHIMANUKI, Hiroyuki ORITA and Toru SATO

ABSTRACT: We determined the level of sodium ceftizoxime (CZX) in the fight atrium and mitral papillary muscle of 22 adults and 6 children undergoing open-heart surgery, 60 and 120 minutes after intravenous administration of this drug at the dosages of 2 grams for adults and 1 gram for children. The CZX level in the fight atrial muscle after 60 minutes was 37.0/*g/g in adults and 51.0/2g/g in children. The CZX level in the papillary muscle of the mitral valve, determined at 120 minutes was 16.9/tg/g. In the present study, we measured the level of the antibiotic CZX in the myocardial tissue during open-heart surgery. The purpose of this was to determine the quantity in which the antibiotic is taken into the myocardial tissue.

KEY WORDS: CZX in myocardium, antibiotic prophylaxis, open-heart surgery

INTRODUCTION

k_Jpen-heart surgery is principally carried out under aseptic conditions, however, since it often involves the use of foreign matter (artificial vessels, artificial valves, patches, etc.), there remains the possibility of infec- tion. Infection occurring during or after open-heart surgery is often intractable and fatal. For this reason, broad-spectrum, highly safe antibiotics are given as a means of prophylaxis in large doses for a long term to patients, post open-heart surgery. It is not rare however, that such antibiotic prophyl- axis leads to bacterial replacement and op- portune infection, as well as granulocyto- penia and other adverse reactiOns such as

The Second Department of Surgery, Yamagata Uni- versity School of Medicine, Yamagata, Japan

Reprint requests to: Minoru Kobayashi, MD, The Second Department of Surgery, Yamagata University School of Medicine, Zao-Iida, Yamagata-shi, Yamagata 990-23, Japan

irreversible disorders in the liver and kidney. Sodium ceftizoxime (CZX) is a third-gen- eration antibiotic of the cephem group. The authors recently administered this agent to patients undergoing open-heart surgery in order to examine its level in myocardial tissue, i.e.: in the right atrial muscle and in the papillary muscle of the mitral valve.

SUBJECTS AND METHODS

A total of 28 patients (22 adults and 6 children) who survived open-heart surgery at the Second Department of Surgery, Yama- gata University from March, 1983 through October 1985, were included in this study. The adult subjects consisted of 2 patients with atrial septal defects (ASD), 2 with ASD + mitral regurgitation (MR), 3 with ischemic heart disease (IHD) and 15 with acquired valvular disease. The surgical treatment given to these patients was as follows: closure of the defect for patients with ASD (2 pa- tients), closure with a pa tch+ mitral annulo- plasty and aorto-coronary bypass grafting for

JAPANESE JOURNAL OF SURGERY, VOL. 18, No. 2 pp. 136-141, 1988

Volume 18 Antibiotic in the Number 2

those with IHD (3 patients). Patients with acquired valvular disease underwent mitral valve replacement (MVR 3 patients), MVR + tricuspid annuloplasty (2 patients), MVR + aortic valve replacement (3 patients), MVR + aortic valveplasty (one patient), AVR (5 pa- tients and AVR + mitral commissurotomy (one patient). The children studied consisted of 3 patients with ASD, 2 with ventricular septal defect (VSD) and 1 with tetralogy of Fallot (TOF). The surgical treatment given to these patient s was; direct closure of the defect for patients with ASD, closure with a patch for those with VSD and a radical operation for the patient with TOF.

The cardiopulmonary oxygenator used for extracorporeal circulation was a Harvey H- 1300 for children and a Harvey-1700 or a Capiox 1143 for adults. In this circulation, b lood was diluted with 20 per cent mannitol (5 ml/kg) and sodium bicarbonate (hemo- dilution rate: 18-25 per cent). Using the core cooling procedure, the rectal temperature of each patient was kept between 24-25~ In addition, the heart was locally cooled. A liquid for myocardial protection (5 per cent glucose 1000 ml + 20 mEq KC1 + 20 ml of 8.4 pe r cen t sodium b ica rbona te : pH 8.32; osmotic pressure 323-331 mOsm/L) cooled to 4.5~ was injected twice--ca. 500 ml at first and ca. 400-500 ml about 20-30 minutes later, after careful checking for the pres- ence /absence of fibrillation after the first injection. This cardioplegic solution was in- jected via the ascending aorta (or directly via the left coronary artery in patients with aortic valve disease). In children, the cardioplegic solution was injected via the ascending aorta at a dose of 10 ml/kg. In this way the myocardial temperature was kept at between 8 and 15~ Furthermore, we endeavored to improve myocardial ischemia by means of implanting a myocardial tissue PCO 2 sensor.

The test drug (CZX) was dissolved in a physiological saline solution (20 ml/dose) and slowly injected intravenously at a dose of 2 g (adult) or 1 g (children). The right atrial appendage and serum were sampled 60

myocardium 137

minutes after medication. In the five patients with mitral valve disease, the papillary mus- cle tissues and serum were sampled 60 minutes after medication.

CZX levels in the collected serum and myocardial samples were measured with a thin-layer disc procedure, employing Bacillus subtilis ATCC 6633. Before measurement, serum samples were diluted with a preserv- ing serum (Consera). A 1/15 M phosphoric acid buffer solution (pH 7.0) was added to the myocardial tissues and the homogenate was left for 60 min, after which it was centrifuged at 3000 rpm for 5 min. The supernatant was then collected, and the CZX level measured.

The above parameters were analysed. Re- sults are expressed as mean + standard error of the m ean (SEM). Statistical comparisons were performed using Student's t test. A p value of less than 0.05 was considered sig- nificant.

RESULTS

The results of this study are summarized in Table la and lb. The CZX level in the right atrial muscle after 60 min was 37.0 _ 2.8 for adults and 51.0 _ 12.4/.tg/g for children. The serum level determined at the same time was 80.9 ___ 7.3/zg/ml for adults and 75.1 ___ 19.5 /zg/ml for children. The serum level was significantly higher than the level in the right atrial muscle 60 min after administra- tion (p<0.005 for adults and p<0.05 for children).

The CZX level in the right atrial muscle, expressed as a percentage of the serum level,

was 44.4 per cent for adults and 64.7 per cent for children, thus showing a good distribu- tion of the drug in the right atrial tissue in both adults and children. The CZX level in the papillary muscle expressed as a percent- age of the serum level was 32.2 per cent, 120 rains after administration. Myocardial tissue was not sampled from the children, but their serum level at this time was 51.2 _ . 12.6 /2g/ml (Figs. 1-2).

138

Table la .

Surg. Kobayashi et al. J ~Ia~c'h 1988

Ceftizoxime Level in the Myocardium and Serum in Adult Patients

60Minutes 120Minutes

No Age BW Atrial Muscle Serum Papillary Serum CZX (Y) (Kg) (/zg/g) (/2g/ml) Muscle (/tg/ml) (mg)

(/2g/g)

1 52 57.5 38.8 92 2000 2 49 74.6 25.0 70 19.1 46.0 2000 3 66 57.0 34.7 74 20.7 37.0 2000 4 56 62.0 39.2 50.7 2000 5 59 50.0 22.1 36.0 13.5 34.1 1000 6 55 52.2 58.6 155.0 9.1 90.3 2000 7 38 45.0 36.8 71.1 2000 8 48 52.6 30.9 58.7 2000 9 48 55.0 40.6 172.0 20.1 92.6 2000

10 44 52.0 62.0 105.0 2000 11 44 55.0 21.3 56.8 2000 12 44 32.0 39.0 61.5 18.2 54.0 2000 13 52 60.0 28.4 74.9 17.6 41.4 2000 14 22 55.0 25.8 50.9 34.9 2000 15 20 65.0 25.6 45.2 39.0 2000 16 56 38.2 65.3 77.1 58.6 2000 17 65 40.2 27.0 70.6 2000 18 51 46.6 24.7 78.2 60.0 2000 19 70 57.0 57.1 124.0 2000 20 49 63.0 27.1 50.7 1000 21 56 53.2 29.0 80.0 2000 22 64 53.0 55.6 125.0 2000

mean 50.3 53.4 3'7.0• 80.9• 16.9• 53.4• 1910 • • • •

In the Adult Cases, the Right Atrial Appendage and Serum were Sampled 60 & 120 minutes After Operation

Table lb. Cefiizoxime Level in the Myocardium and Serum in Children

60 Minutes 120 Minutes No Age BW Atrial Muscle Serum Serum CZX

(Y) (Kg) (/2g/g) (Bg/ml) ~ g / m l ) (mg)

1 6 15.7 44.1 181.0 115.0 1000 2 6 21.0 33.0 50.7 20.2 1000 3 4 18.3 34.1 48.6 30.8 1000 4 6: 1.7.4 27,2 48.0 36.6 1000 5 3 14.0 117.0 65.7 58.1 1000 6 5 17.0 50.6 56.5 46.2 1000

mean 5.0 17.2 51.0__.12.4 75.1+19.5 51.2• 1000

• • •

The means of the two groups (adult & child) of patients showing age, body weight and CZX content in myocardial and papillary muscle. Adults and children were given 2 gm and 1 grn, respectevely.

Volume 18 Antibiotic in the myocardium 139 Number 2

100

90

80

~*~ 70

5O

rD M 30 M

20

10

-p<0 .005 ]

- .Z .

(1) l<2)

60 minutes

(1) atrial muscle (2) serum (3) papillary muscle (4) serum

-p<O.Ol -~

T

(~)

120 minutes

after CZX administration Fig. 1. Time course of CZX content in

serum and myocardial tissue. Adult pa- tients

100

90

8O

N 6o

~ 5o N ~ 40

30

20

10

[---NS---] ~ : Child

/ ]- I I" Adnlt

:::::::::::::.:|

i:!:?:?:?:?~:~:l I "[ ::ii::iiiiiliiiill .... t ,

:i:i:i:i:i:i:it ::::1:::::::::'1 ;:::::::::::.:.

iiii::::iiiii::i::t ~i?i?i?i?i?:?:t

60minutes 120minutes after CZX administration

Fig. 2. Time course of CZX level in serum.

D I s c u s s I o N

Antibiotics, which are usually prescribed for the inhibition of bacterial growth follow- ing inflammation and for prophylaxis of

post-operative infection, are used for the prophylaxis of infection in most patients undergoing open-heart surgery. However, in spite of the prophylactic use of antibiotics, the postsurgical infection rate is as high as 12.7 per cent according to Goldman et al., 1 or 8.6 per cent according to Fong et al3 Fur- thermore, a recent t rend in the number of aged patients receiving open-hear t surgery is increasing, and the incidence of postopera- tive wound infection is now as high as 4 per cent according to Akiyama. s Endocarditis is reported to be caused mainly by Gram- positive bacteria like Staphylococci or hemo- lyric Streptococci.* Prosthetic valve endocarditis (PVE) is an infrequent complication of car- diac valve replacement but one with serious consequences, s-7 In a recent study from Massachusetts General Hospital, the inci- dence of PVE after primary valve replace- ment was 4.4 per cent over a mean follow-up time of 39.8 months; the actuarial risk of PVE being 5.7 per cent over 60 months? Many data have been published to evaluate the utility of various antibiotics for the prophyl- axis of infection following open-hear t sur- gery. a-n In these published studies, the myo- cardial level of antibiotics was examined only in the right atrium, and hemodilution of cardiopulmonary bypass is not considered. The reported levels therefore do not seem to represent correct myocardial levels of anti- biotics. Generally, the hemodilution rate of extracorporeal circulation is 15-25 per cent. In this study, soon after clamping the aorta, 8 to 10 ml /kg of~cardioplegic solution was infused into the aortic root at a pressure of 50-80 mmHg. In the light of such hemodilu- tion, it is doubtful whether the levels re- ported so far, present the correct tissue levels of antibiotics. As far as lung levels of third- generation antibiotics are concerned, Kuri- bayashi et al? ~ reported a CZX level of 17.3 /xg/g 120 minutes after administration, and Orita et alY reported a latamoxef (LMOX) level o f 22.4/~g/g at the same point in time. In this study we recognized that the CZX level contained in the papillary muscle of the

140 Kobayashi et al. Jpn. J. Surg. March I988

mitral valve, 120 minutes after i.v. administra- tion of 2.0 g CZX was 16.9 • 1.4/~g/g. D u r i n g aortic clamping, the myocardial blood is supplied by noncoronary flow, therefore, the observed high CZX level, even after aortic clamping, indicates that CZX probably ac- cumulates in the myocardium more densely than in any other tissue. In general, it is well known that myocardial blood is supplied from the coronary artery, myocardial arte- rioles, and the sinusoid and capillary bed. When cardioplegic solution is injected via the aortic root after aortic clamping, the antibiotics in the blood vessels are washed out by the solution. As the CZX level in the papillary muscle was as high as 16.9/2g/g after the injection of the solution, it is suggested that this antibiotic is reasonably effective in the treatment of endocarditis, According to Nishida, CZX is a distinctive new parenteral cephalosporin antibiotic with a broad antibacterial spectrum which is more potently active against a wide variety of Gram-negative bacilli, Staphylococcus aureus and Streptococcus ~4 (Table 2). We expect that CZX may provide effective prophylaxis in patients having open-heart surgery.

In the pathogenesis o f endocarditis, Strep- tococcus viridans still occupies a principal share. In recent years, however, an increas- ing incidence of S. aureus, S. epidermidis, S. viridaus, Gram-negative bacilli and Enterococci has also been noted. ~-7 In terms of anti- bacterial activity, CZX is less potent against S. viridans than is penicillin G, but it is highly effective against S. aureus (MIC 80, inhibition concentrat ion against a clinically isolated strain: 3.13 gg/ml) and H. influenzae (MIC 80:0.05/tg/ml).

Even 120 minutes after intravenous ad- ministration, the myocardial level of CZX was larger than the MIC for most of the pathogens.

According to a report made at a recent drug symposium, the serum CZX level fol- lowing 1 g intravenous administration was 114.8/~g/ml after 5 minutes and 31.3/~g/ml after 60 minutes. Its half-life was 1.29 hours.

Table 2. Protective Effect of Ceftizoxime on Mice Infections

Mucin Ceftizoxime Organism % EDs0; mg/kg

S. aureus 47 4.03 5 (2.0 X 107/mouse) (1.20~9.30)

S. aureus 44 3.53 5 (5.3 X 107/mouse) (1.69~5.94)

E. coli 29 0.020 2.5 (1.2 X 104/mouse) (0.006--0.031)

P. mirabilis 73 0.255 5 (2.1 X 107/mouse) (0.141--0.401)

P. vulgaris 63 5 0.038 (9.4 X 105/mouse) (0.025~0.061)

S. marcescens 31 4.28 5

(4.9 X 10*/mouse) (2.75--7.57)

P. aeruginosa 93 5 50.1 (3.7 X 104/mouse) (23.4"-'127)

Mouse; ICR strain, male, 4w (20.0 + 1.5 g) 10 mice/group. Infection; 2.5 or 5% mucin suspension, i.p. ( ); 95% confidence limit.

The same level after 2 g administration was 70.5/2g/ml after 60 minutes and 31.3 ~lg/ml after 120 minutes, according to Nishizawa et al., is or 55.8/lg/ml after 60 minutes and 33.1 /~g/ml after 120 minutes, according to Asahi et al. TM The serum CZX levels obtained by our study involving the intravenous administra- tion of 2 g CZX to adults and 1 g to children were slightly higher than the above men- tioned levels, i.e., 80.9/tg/ml after 60 minutes and 53.4/ lg/ml after 120 minutes in adults, and 75.1/2g/ml after 60 minutes in children. In our study, the CZX level was 44.2 per cent for adults and 64.7 per cent for children. Furthermore, the CZX level in the right atrium tissue 120 minutes after administra- tion (i.e., after aortic clamping) was still as high as 30 per cent or more of the serum level. The fusion and shortening of papillary muscle can be recognized in mitral valve replacement cases and in our study it was recognized that CZX was accumulated in this tissue. An effective antibacterial action is

Volume 18 Number 2 Antibiotic in the myocardium 141

thus e x p e c t e d in o p e n - h e a r t surgery.

( R e c e i v e d fo r p u b l i c a t i o n o n Nov. 10, 1986)

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2. Fong IW, Baker CB, McKee DC. The va/ue of prophylactic antibiotics in aorto-coronary bypass operation. J Thorac Cardiovasc Surg 1979; 78: 908-913.

3. Akiyama K, Endo M, Koyanagi H. Coronary arterial surgery in aged patients. Jpn J Thorac Surg 1982; 35: 417-422.

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Prophylactic antibiotics in closed heart surgery. Chest 1971; 60: 252-255.

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