oxacillin

hf. J. Gynecol. Obstef., 1989, Suppl. 2: 29-34 International Federation of Gynecology and Obstetrics

Periqxrative

a

sys’ienk

infections in breast mezlocillin/oxacillin

29

surgery:

su

K. EngeP and A. Wildfeuerb ‘Department of Obstelrin and Gynecology, Univerwy of Heidelberg, Herdelberg and Wepartmenr of Theoretrcol Medicine, Universiry of (F.R.G.)

Urn. Ulm

Abstract In a prospective, randomized, open trial, effiracy of one dose of sulbactam/ampicillin (I g : 2 g) was compared to three doses of mezlocillin/oxacillin (2 g : 1 g), starting with induction of anesthesia in 80 breast surgery patients with an increased risk of postoperative infection. No infections at the site of operation were seen in either group. Fever due to postoperative pulmonary tions occurred in one patient in

complica-

the sulbactam/ampicillin group. The only side effect was a moderate exanthema observed in one patient in the mezlocillin/oxacillin group. In this study of the prophylaxis of patients with an increased risk of postoperative infections having the potential to jeopardize the results 0-f .wrRery a single dose of suibactam/ampipillin Wnsosefj‘eci;‘;,

n- I -LO-* .“,... t0rm m.,rm *E “.UL4.>kj,

.” ..I_‘I,

thrtic doses of mezlocillin/oxacillin. Keywords: Prophylaxis; Breast surgery; Sulbactam; Ampicillin; Mezlocillin; Oxacillin. Introduction

The role of systemic antibacterial prophylaxis for reduction of postoperative infections following intraoperative bacterial contamination has been well established 141. Major indications are gynecological, obstetrical, and colorectal surgery. In breast surgery, how0020-7292/89/$03.50 0 1989 International Federation of Cynecolow and Obstetic. Published and Printed in Ireland

ever, the efficacy of antibiotics given prophylactically, is difficult to assess, since no hard data are available. General infection rates witb al!oPlastic prostheses range from less than l-S% [5,7,&I].Over the last 5 years,

an increasing number of surgeons have expanded their use of systemic antimicrobial prophylaxis [13] because infection may severely compromise the quality of the surgical result. Apart from the different surgical procedures, individual factors and/or impairment of the immune system may increase the risk for postoperative infection [20]. This study was designed to compare the

prophylactic efficacy of a single dose of sulbactam/ampicillin with that of a short term, three dose course of mezlocillin/oxacillin in breast surgery patients suspected to be at “high risk” for developing infection at the &.UPL~YCsire. Suibactam is a new semisynthetic compound which irreversibly inhibits beta-lactatnases, and extends the spectrum of the penicillins [lo,251 to cover the otherwise resistant strains of organisms normally isolated from wound infecticns. The combination of mezlocillin/oxacillin with a similar antibacterial spectrum, had been previously administered as a routine “short term” prophylaxis at our institution. Materials and methods Patients Between August 1987 and February 1988, a

30

En@let al.

of 80 patients, considered to be at high risk for developing infections after breast surgery, were entered in this prospective, randomized, and open study. The patient inclusion criteria were absence of present infection, no recent antibiotic therapy, no

total

known normal

allergy to pcnici!Sins, hepatic and renal

not pregnant, function, and

informed consent. J ntibiotics Patients were randomly assigned to one of the two treatment groups using a computergenerated randomization list. Forty patients received sulbactam/ampicillin (1 g : 2 g) as a single dose treatment, and 40 patients received oxacillin/mezlocillin (1 g : 2 g) as a short term treatment consisting of three doses, 8 h apart. In both groups, treatment aas started with induction of anesthesia and administered as infusions for 15 min. Sampling Blood samples were taken before and at various time intervals after the end of infusion. Serum was separated by centrifugation at 4% and stored immediately at - 70% Skin and subcutis tissue samples were taken if available during the surgical procedure, rinsed with saline, stored at - 70°C.

dried

between

gauze,

and

Assay Serum and tissue samples were assayed not later than 6 weeks after collection. The deep frozen samples were carefully homogenized (Microdismembrator II, Braun Melsungen, FRG) prior to drug analysis [12,231. The concentrations of sulbactam were determined by gas chromatography with mass spectrometry detection (W-MS) [ll]. Ampicillin was analyzed using a microbiological cylinder plate technique with Sarcha lutea ATCC 9341. Clinica!cwluation Patients were evaluated daily while hospitalized for signs and symptoms of infection at the site of operation. Febrile morbidity was Int .I Gynecol Obstet SUPPI2

defined as an elevated body temperature, >38W for more than 2 days excluding the first postoperative day. Toxicity All possibly related antibiotic side effects were recorded daily. Routine laboratory tests were performed before the operation ak,J between the 3rd and 5th postoperative days. These included complete blood count and differential, platelets, total bilirubin, transaminases, serum creatinine, alkaline phosphatase, gamma-glutamyltransferase, blood glucose, and Quick’s value. Results Group comparability There were no statistically significant differences between the two treatment groups (sulbactam/ampicillin versus mezlocillin/ oxa5llin) in terms of age (44.2 vs. 46.1 years), weight (63.4 vs. 62.2 kg), or height (163.4 vs. 163.5 cm). There were also no differences between the treatment groups in terms of surgical indications (Table I), or in terms of procedures according to the preoperative “high risk” category (Table II). The operating time in minutes was significantly longer for the sulbactam/ampiciUin group (168 min) than for the mezlocillin/oxacillin group (118 min) (P = 0.039).

Table 1.

Surgicalindicationsin patientsenteredin the study. Sulbactam/ ampicillin 00

MeAocillin/ oxacillin 00

Primarily esthetic Carcinoma of the breast Primary treatment. breastcutserving therapyand local R~“~WlL~~ Breastreconstruction Other

11

8

12

12

13 4

17 3

Total

40

40

-

Clinical efficacy During the postoperative course, no infections at ihe site of operation OCCUri& in either group. One patient developed fever following sulbactam/ampicillin prophylaxis due to a minor pulmonary complication. In total, both regimens of antibiotic prophylaxis were successful. There were no failures. Without implanr Locally extensive. long O~ttthS time Two stepprocedure Chemotherapy.diabetes

13 7 2

9 6 3

Pharmacokinetics of sulbactam and The concentrations ampicillin in serum, cu’is, and subcutis were maintained at a nearly constant ratio of approximately 1 : 2 at various times intervals after administration (Table III). Basically the ratio remained the same during penetration from blood to tissues. Concentrations of both substances in the subcutis were about 5-10 times lower than in the cutis. The concentrations of sulbactam and ampicillin decreased more rapidly in serum than in the cutis resulting in similar levels in serum and &sues between I and 3 h after infusion.

Cufis(n = 16) SUlU~CtCUll Ampicillin subculis(n = 8) Sulbactam Ampicillin

IS.0 * 7.0 32.3 e 13.6

2.4 k 2.8 f

‘Mean time after infusion (min f S.D.).

4.3 4.8

Toxicity No clinical side effects that could be related to sulbactam/ampicillin treatment were observed. In the mezlocillin/oxacillin group, one case of mild exanthema that responded quickly to symptomatic treatment was observed. The evaluation of various Iaboratory parameters revealed no specific postoperative toxicity and there were no significant differences between the treatment groups. Discussion Infection after breast surgery represents a substantial risk that compromises the quality of the surgical result. Breast surgery is a potentially unclean procedure as investigatlons by Ransjo et al. [16] have shown. In more than 90% of their breast tissue samples obtained durin_~=llrgery, bacteria were found. The predominant organisms were Stuphyfocecrt~ epidermidis and proprionibacteria.

10.9 -c 6.2 20.6 f 12.3

1.4 + 1.9 f

2.0 3.5

5.0 f 4.4 8.3 = 6.2

1.0 + 1.1 0.7 f 0.9

32

Engel et a!.

These aerobes and anaerobes were sensitive to penicillin and isopenicillin. Little is known about the role of bacteria in the non-lactating female breast. Isolates from the exprimate of the nipple suggest that the mammary ducts are the habitat of various microorganisms. It has been speculated that colonization or clinically silent endogenous infection may lead to clinical infection in certain breasts if activated by the surgical procedure. Apart from sporadic infections with aUoplasGc implants caused by mycobacteria [6,19], other organisms isolated were mainly Staphylococcus epidermidis and some Proteus mirabilis, Staphylococcus aureus, and Pseudomonas aeruginosa 1241. Once infection has occurred, complex mlvage procedures are required including topical antisepsis, intermittent or continuous irrigation systems, contracture release, and reimplantation of a double lumen prosthesis containing antibiotics [18,24]. Removal of the prosthesis may still become necessary. It has been suggested that chronic infection may be a cause for capsular contracture of breast implants [1,21]. The role of systemic antibacterial prophylaxis, however, remains unclear. That the frequency of wound contamination via air and skin increases with the duration of the surgical procedure, has been shown by several investigators [2,3]. Other local factors such as necrotic tissue, hematoma, or localiy decreased skin perfusion following radiotherapy, also contribute to the risk of postoperative infection. The prophylactic use of new broad spectrum penicillins and cephalosporins in radical mastectomy patients has been advocated by several investigators [15,22]. With an increasing number of patients undergoing highly individualized breast conserving therapy for invasive carcinoma ~,f the breast, surgical procedures have become more and more differentiated. Initial excisional biopsy is often followed by a two step surgical procedure. Depending on the histological findings, a modified radical mastectomy with or without primary reconstrucInt J Gynecot Obstet Suppt 2

tion, or a definite breast conserving treatment is indicated. In the iatter case, according to the individual situation, extensive mobilization and reconstruction of the mammary gland including contralateral mammaplasty is often indicated. Apart from this, postoperative radiotherapy may be an additional factor making breast conservation a high risk procedure for the development of infection. This represents a substantial threat with poor local healing and retraction of scar or mammaqgland leading to a poor cosmetic result 191. Other risk factors such as obesity, o!d age, chronic steroid medication, and chemotherapy may also contribute to an increased risk for the development of postopero;ivc izfections due to impairment of the immune system [20]. In the present study, patients given two different regimens of perioperative prophylaxis with systemic antibiotics developed no acute infections. According to the different indications and surgical procedures performed on these patients, they were considered to be at high risk for the development of infections at the operative site. Single dose prophylaxis with sulbactam/ampicillin proved to be as effective as a three dose regimen of mezlocillin/oxacillin in terms of clinical effectiveness and side effects even though the mean duration of the surgical procedures of the patients given sulbactam/ampicillin were significantly longer than those patients given mezlocillin/oxacillin. Pharmacokinetic determination of sulbactam/ampicillin concentrations during breast surgery revealed serum and cutis levels that are effective against beta-lactamase producing aerobic and anaerobic bacteria most likely to be involved in breast infections. Par these species, i.e. S. aureus, B. fragilis, S. epidermidis, and P. mirabilis, the MIC, of sulbactam/ampicillin ranges from 0.5 to 4 pg/ml of ampicillin [171. These concentrations are exceeded by the serum and tissue concentrations observed in this study (Table III). Sulbactam and ampicillin showed similar characteristics in serum and tissue levels with

Breas~surgeiyprophylmir

a nearly constant sJbactam/am~icillin ratio of appioximately 2 : 1 hitdifferent time intervals after infusion. This distribution is pharmacologically eJsential for the continuous interaction of both compounds. The role of antibiotic prophylaxis in bleast surgery is difficult to assess. A recent survey [13] showed that t1je number of plastic surgeons in the United States who always or often use antibacterial prophylaxis in breast surgery has increased over the last decade. The percent of plastic surgeons using it in mammaplasty was 59,7o in augmentation and 44% in reduction, and in breast reconstruction it was ti66% with implants and 53% with flaps. Nevertheless, about one third of all plastic surgeons still never use prophylactic antibiotics.

4

5

6

7

8 9

10

Conclusions Apart from the well known risk factors, the general medicolegal climate and its implications has led to a wider acceptance of prophylactic antibiotics in breast surgery, although its indications and limitations remain to be clearly defined. It is difficult to generate hard data through placebo controlled studies because physicians and patients prefer not to be exposed to the risk that may be associated with the use of placebo in these surgical procedures. The results of the present study support the view that single dose antibiotic prophylaxis using sulbactam/ ampicillin is clinically effective as well as cost effective and its benefits probably outweigh its potential hazards in higl: risk breast surgery.

11

12 13

14 15

16

17

References 18 Asphmd 0: Capsular contraction in siticone and salinefiicd breast im&xnts after reconstrwtion. Plast Rcsonstr Surg 72: 270.1984. Benediktsdottir E. Hambraeus A: Isolation of anaerobic and aerobic bacteria from clean surgical wounds: an expcrbnentai and clhdcal study. J Hosp Infect 4: 141, 1983. Benediktsdottir E, Kolstad K: Non-sporeforming anaero-

19

20 21

33

bit bacteria in clean surgical wouuris- air ana run contaminations. J Hosp Infect 5: 38.19g4. Burke IF. The effective period of preventive antibiotic action in erpzimcnrai ixi.siors aad dermzl !esiws. SurSeryJO: 161,1%1. de Cholnosky T: Augmentation mammaplasty: survey ot complications in 10,941 patients by 265 surgeons. Plast Refonstr Surg 45: 573.1970. Clegg HW. Foster MT, Sanders WE, Baine WB: Infection due to orgardsms of the Mycobacwium fortuiium complex after augmentation mammaplasty: clinical and epidermologicalfeatures. J Infect Dis 147: C27.1983. Courtiss EH. Goldwyn RM, Anastasi GW: The fate of breast implants with iufections around the-m. Plast Reconstr Surg 63: 812.1979. Cronin TD, Greenberg RL: Our experiences with the silastic gel breast prosthesis. Plast Reconstr Surg 4/i: 1. 1970. Engel K, Muller A. Kaufmann M, v Founder D: Cosmetic results following breast consewiag therapy. In Breast Diseases (eds F Kubli et al.) in press. Springer-vcrlag, Berlin, 1989. English AR, Retsema JA, Girard AE et al: CP-45.899, a beta-lactamase inhibitor that extends the antibacbxiai spectrum of beta-lactams: initial bacteriological charactrrization. Andmicrob Agents Cbemothn 14: 414 1978. Foulds G, Stankewicb JP. Marsball DC et al: P&macokinetia of stdbactams in humans. Antimicrob Agents Chetuthn23: 629, 1983. Kavaaagb F: Analytic Microbiology, Vol 2. Academic Press, New York, 1972. Krizk TJ, Kou N. Robsoo MC: The current use of prophylactic antibiotics in plastic and reconstrwtiv: surgery. Plast Reconstr SurgSS: 21.1975. Krizek TJ, Gottlieb LJ, Koss N. Robson MC: The use of prophylactic antibactcrials in plastic surgery: a 19805 update. Plast Reconsa Surg 76: 953.1985. Mizuta E. Kaneko Y. Nilindei H et al: Pharmacokinetits of cefotiam in the exudate ‘iom wounds of patients with breast cancer operated upo,, for radical mastectomy. Jpn JAntibiot39: 109, 1956. fiansjd U. Aspiund OA. Gylbert L. iwell 0: Bacteria in thL female breast. Stand J PIast Reconstr Surg 19: 87, 1985. Retscma JA. English AR, Girard A et al: Sulbacta?/ ampicillin: in vitro spectrum. potency. and activirg in models of acute infectios. Rev Infect Dis. SuppI 8: 528, 1986. Rigg BM: A continuous breast irrigation system. Plast Reconstr Surg 78: 102.19%. Safranek JT. Jarvis WR, Carson LA et al: Mycoboeferium chelonce- wound infections after plastic surgery employing contaminated gentian violet skin-marking solution. NEngl J Med317: 197.1987. Schenan M, Kalisman M: Complications of breast rcconstrwtion. Clin Pla.stSurg II: 343.1984. Shah 2, Lehman JA. Tan J: Does infection play a role in

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breast capsular contracture? Plast Reconstr Surg 6R: 34. 1981. Tsuburayo H, Watanabe I, Takahashi M, Endo S: A clinical study on penetration of aspoxipetiicillin into tissue and wound exudate in breast cancer. Jpn J Antibiot 38: 1515.1985. Wildfeuer A, Lemmc JD: Pharmacokinetics of josamytin. Ann&n-Forsch 35: 639. 1985. Wilkinson ST, Swartr BE, Toraoto RI: Resolution of Iate-developing periprosthetic breast infections without prosthesis removal. Acsth Plast Surg 9: 79.1985.

Int J Gynecol Obsfer SuppI

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Wise R. Andrew JM. Bedford KA: Clavolanic acid and CPX.899: a comparison of their in vitro activity in cotttbinatioo with penicillins, J Antimicrob Chemother 6: 197, 1980.

Addms

for rcgdttts:

K. Engel

Deputmcat of

Obstetriu Unlver<y OFHeidelberg Heldelbq, FRG

and Gyoecology