Outcome Analysis of Antimicrobial Prophylaxis in Cardiothoracic Surgery Patients Receiving Cefazolin Alone or a Ceftazidime—Vancomycin Combination Joseph ©. Brooks, Pharm.D., BCPS,* Randy C. Hatton, Pharm.D., FOCP, BCPS,t and Larry Winner, PRO" ‘Abstract — Athough cefazoin is recommended as the drug of choice for most cardiothoracic surgeries, some surgeons prefr a broed-epecrum prophylactic regimen, The purpose ofthis observational study was to compare the infection rales in a cohort of mate pationts undergoing hear, ung, an thoracic aneursym surgeries from 1995 to 1998 ala singe institution who received cefazolin, cet- tazidime plus vancomycin (broad-spectrum), or other antibiotics for antimicrobial prophylaxis, Data wore collated for 648 patonts over more than 2 years, Infec- tion rates were not different (p = 0.5) between the cefazolin (14%) and the broad-spectrum antibiotic groups (11%). The incidences of mediastinitis were also not alferent between the cefazoln and broad-spectrum groups. There was 2 statistical shorter length-o-stay inthe ICU (p = 0.0109) n the cefazolin group {mmecian 2.0 days) compared withthe broad-spectrum group (median 3. days) ‘when phases | and I! were combined. Muitipe logiatc regression suggests that antibiotics were changed more often in the patents who received cefazolin instead of ceftzidime plus vancomycin, Other variables associated with the need to change antibiotics include surgeon, open-heart surgery, diabetes, and hospital stay greater than 1 day. These data convinced the cardiac surgeons at this insulin to use cefazolin asthe cg of choice for cardiothoracic surgery antbioic prophylaxis. Key Words — entimicrobial prophylaxis; cefazolin; ceftazidime; vancomycin Hosp Pharm — 2002:37:380-385 “Cinial Pharmacy Specalt inthe Carcothoreclo Surgery Unita th Malcclm Randat Vet- ‘rans Afars Medical Center in Gelnosvilo, FL end Canical Assistant Professor for tho Uni- versity of Florida, College of Pharmacy; Co-Director, Drug Information and Pharmacy Resource Center, Chanda at tho Univeraty of Fleride, Calncovile, Fl and Ciel Professor for the University of Farida, College of Pharmacy, “Lecturer, Department of Statistics, Uni- voralty of Florida, Galnosvilo, FL. ‘Addracs coneepondenco and reprint requests to Dr. Brooks atthe Department of Phar- ‘acy (119), Malooim Randal VA Medal Center, 1601 SW Archer Road, Gainesvila, FL 32808-1197. Parts of this shidy were presented In a poster presentation atthe American Society of Health-System Pharmacists Annual Meeting at Reno, Nevada in June 1989, BACKGROUND Guidelines for antimicrobial pro- phylaxis in cardia ‘and thoracic surgory Patients have long recommended csfe- zolin as the drug of cholce.'* Vane comycin is recommended only when an insituion has a history of methcilin- resistant Staphylococcus aureus and ‘Staphylococcus. epidermidis infectons ‘or when patients are allagie to penk- ciline or cephalosporins. single dose ‘of antibiotic fs recommended unless the eurgery is prolonged, then an adeitional dose may be given, The use of antibiot- ic prophylaxis for more than 24 hours could lead to resistance or superinfeo- ton, In practice, however, cardiac sur- enns often use henad-spactrim ant oc prophyiacte coverage andior pre- scribe prophyiactic antibiotics for a Jonger petiod in an attempt to decrease the incidence of perioperative infec- ‘tons, Surgeons at this nsturton began using broad-spectrum prophylaxis, that 1, vancomycin plus ceftazidime, for car- dlothoracic surgeries based on isolated cases of gram-positive and gram-noa- tive wound infections. They continued their practice of prescribing “prophylec- {ic™ antibiotics unt all drains were pulled. Therefore, most patients were reuxiviny prolonged courses of broad spectrum antibiotics for cardiothoracic surgery prophylaxis. Whether prolonged broad-spec- trum antimicrobial prophylaxis in crdio- 380 Volume 37, April 2002thoracic surgeries would result in better patient outcomes led us to prospective- ly monitor patients who underwent car- diothoracie surgeries. The objective of this study was to determine whether infection rates and the need to change antibiotic regimens were dliferent when 1a broad-spectrum antibiotic combina tion was used instead of cofazotin, METHODS ‘This observational study concur rently collected data for male patients undergoing hear, lung, and thoracic aneurysm surgeries from July 1, 1995 to June 30, 1998 at a single inctitution. This time period was divided into three segments based on surveillance report- ing to the hospital's Pharmacy and Therapeutics Committee. Usual doseges of antibiotics were cefazolin 4 g IV every 8 hours, ceftazidime 1 g IV every 8 hours, and vancomycin 1 g IV ‘every 12 hours. These dosages were adjusted based on renal function and trough vancomycin serum concentra- tions. During the baseline period June 1, 1995 to December 31, 1996, most pationts racelved a combination of cof tazidime plus vancomycin, Based on data from this baseline period, which was reviewed by the Infectious Disease Committee and the Pharmacy and Inerapeutes Committee at this institu tion, cefazolin was promoted as the pri- ‘mary antibiotic for antimicrobial prophy- taxis in phase |. Phase | was conducted from January 1, 1897 to September 30. 11997. This monitoring period was estab- lished to evaluate whether cefazolin provided effective antimicrobial prophy- lexis, During this petiod, cefazolin was cused fi the najily of eases, bul there: was stil considerable use of the cof tazidime plus vancomycin combination. Phase Il took place from October 1, 1997 to June 30, 1998. In this phase, patients primarily received cefazolin for antimicrobial prophylaxis as it became the consensus agent of choice based fon data from phase |, Antimicrobial Prophylaxis in Cardiothoracic Surgery Patients Data about each patient's demo- ‘graphics, treatment, and outcomes wore prospectively collected. Data Included age, weight, body surface area, days in the hospital before surgery, concomitant diseases (eg, die- bbotes, hypertension), type of surgery (bear, lung, cardiac valve Topairiroplacement, or thoracic ‘aneurysm, and surgeon. Cardiac surg cries were further classified a8 open heart vs closea-heart and by the num- ber of vessels for coronary artery bypass surgeries. Tho intraoperative cross-clamp and bypass times were recorded, The type of antimicrobial pro- phylaxis was recorded as cefazolin, cof- tazidime plus vancomycin, vancomycin atone of with another antibiotic (not cof- tazidime), end as “other” single or com- bination antibiotics. Outcomes recorded included whether or not there was @ post-operative surgical infection andthe lenath-of-stay in the surgical intensive care unit fthe patient developed endo- carditis oF mediastinitis, the organisms that were cultured with sensitivities were recorded. ‘A change in antibiotic therapy was ‘examined 9s an exploratory variabio that would act as a surrogate for infec- tion. This logic was used because the attending physicians fet these patents ‘were no longer being adequately treat- fed by their antiiouc regimen, Antimi- ‘robial prophylaxis was considered the antibiotic that was used before surgical Incision, during surgery, and after ‘surgery until all chest tubes were removed, Ceftazidime plus vancomycin was often used in patients thet had been in the hospital for more than 3 days. Patients whi lta Lew hospital fr more than 3 days were considered col- ‘nized with nosocomial bacteria. How- ‘ever, there was variation inthis practice bbased on surgeon preference and histo- ty of penicitin atlergy. ‘The variabilty in antibiotic selection allowed for comparisons between pro- phylactic regimens, Cescriptive statis- tics are presented as means and stan- dard deviations. Non-normally detrib- Uted data are presented 2s medians. A Univariate analysis of nominal demo- ‘graphic and outcome variables (eg. infection) was done by two-tailed chi- equare or Ficher's oxact teste, dopend ing on whether the data met the assumptions of the chi-square test. Continuous demographic and outcome variables in phases | and Il were ana- lyzed using an unpaired Student's ttost (of Mann-Whitney U test for non-normal- ly distributed data. All tests were done with an alpha level of p < 0.05, Because this was an observational ‘study, there are many variables that ‘could be potential confounders for the need to change antibiotics. Exploratory analysis was done with multiple logistic regression analysis to determine whether the incidence of changing antibiotic regimens was related to a ‘group of possible covariates. The fol lowing were considered: surgeon (3 eur- geons); age (< 60 years of age or G0 years of age), body surface area (< 2 m* ‘or 2m’); cross-clamp time ( 60 min- tutes oF > 60 minutes); diabetes (pres- ‘ance or absence); days in the hospitat before surgery ( 1 day or > 1 day); and surgery type (lung, closed-heart, or open-heart). The multiple logisti regression models related the probabil ty ota change in antiaties to the above independent variables using the GEN- MOD procedure.’ Because the sample size was relatively small, an alpha of increase the power of detecting var- ables associated with the need to ‘change antibiotics. Negative regression cooticionts suggest the need for fewer anliiole changes. Ouds rallvs end 190% confidence intervals were catculat- ‘ed for varigbles associated with an increased need to change antibiotics. RESULTS Data were collected for 648 cardio- ‘horace surgery patients over a 2.2- year period. Table 1 describes the Hospital Pharmacy 381seseseaeeaeae Antimicrobial Prophylaxis in Cardiothoracic Surgery Patients vancomycin group (9 = 0.5). ‘There were na documented cases Pationt Variables ‘of endocaris or mediastinsin any of tho patients who received valve Sd Go Phase | teplacements. Eight patients who had Age (ears) 58202 _ 64.3 #102 developed mediastinitis, were in the ‘Weight (ko) 0522159 0694 108 coh eas” won| tars bees Body Surface Area (n?) #02 21x02 surgery, while four patients were inthe Diabetes 5) 26.3% 37.0% hospital more than 3 days before Hypertension (%) 63.8% 642% surgery. One patient (0.3%) in phase | Carsiae Surgery T= 141 (95%) _n=137 (79%) | TErdived coftazidime plus vancomycin ‘CABG laa n= ‘So J n St 7 and seven patients (2.4%) in phase I! No. of Vessels 35#12 35210 received cefazoin. Five of the seven Labret il pene am patients who developed mediastinitis Nets) nt Zt Oe Catazotin grew methiciin-esistant Thoracic Aneurysms nS =4__| Staphylococcus aureus, one grew E. Lung Surgery (%) (6%) n= 32 (19%) hormaechei, and one grew S. Hospital Days Before Surgery 3826.3 45268 ‘marcescens. All of these organisms median 0 median 20___| were resistant to cefazain. All seven Knit Popylas GH ——SCSCSCSCSSCSCSCSCSSS ite pationts were eiabetc and had Cefazolin 28% same 60% elevated serum glucose concentrations Ceftazidime-Vancomycin 59% 40%" 10%" in the postoperative period. The patient Other ae ge fie who developed mediastinitis on cof- Vancomycin 71% ah 14% : ercomyoin 78 AA __10% | tazcime plus vancomycin grew methi- Gross Clamp time (min) 78.5 £27.0 71.9303 | citin-esistant Staphylococcus aureus. Bypass Time (min) 11204300 11332443 | A patient stated on cafazatn, but who tp = 0.0823 eventually recelved many different p= 0.0012 ‘ntibiotics, developed endocarditis that “Phase | vs, Phase Il, p = 0.0079, Mann Whitney U- was determined to be methicillin-resis- “Baseline vs Phase |, p < 0.0001 tant Staphylococcus aureus, which ‘Phase | vs. Phase Il, p = 00085 exhibited tolerance to vancomycin. ‘Basaline vs. Phase Ii, p < 0.0001 “There ware na detactahiacliferanco in ‘Besalne ve Phase i, P= 0.0002 the incidences of medastinis (p = Bae gated tapi (0.57) or endocardits between the cefa- ‘Baseline ve, Phase |, p = 0.0016 olin and ceftazidime plus vancomycin "Phase | vs. Phase Il, p = 0.0001 ‘treated patients, Inere was @ stausucary shoner patients included forthe three phases of this study. The only demographic vari= ables that wore statistically different between phase | and phase II were the prevalence of diabetes, which was high- ‘erin phase Il, and tung surgery, which ‘was aso higher In phase I. ‘The use of cefazolin for cardiotho- racic surgery prophylaxis increased sta- tisticaly in each consecutive phase. ‘The use of ceftazidime plus vancomycin ‘vancomycin alone or in any combina tion decreased in each consecutive phase. Univariate analysis found no statis- tically detectable diferences among the cefazolin and ceftazidime plus van- ccomycin groups in the rats uf pastop- erative infections (Table 2). If all three phases were combined, the rates of Infection were 14% In the cefazolin ‘group and 11% in the ceftazidime plus {ength of stay n the intensive eare unit (= 0.0108) in phase I (4.9 + 8.9 days, mecian 2.0) compared with phase I (7A £ 128 days. median 3.0). When phases | and Il are combined and the lengths of stay for patients who received cefazolin are compared with those who roceived ceftazidime plus vancomycin, Une patients wh revived broad-spectrum coverage had a longer length of stay (ie, 62 + 1.0 days [medi- ‘an 2.0 days] for the cefazolin group compared with 7.7 # 11.3 days [median 382 Volume 87, April 2002Antimicrobial Prophylaxis in Cardiothoracic Surgery Patients \Vatiables Used in the Multiple Logistic Regression Models, 3.0 days] for the ceftazidime plus van- comycin group, p = 0.0014). ‘The percentages of each indepen- dent variable used in the miatiple logic regression models ar listed in Table 3. Because not ail independent variables were available forall patients, estimates of regression coefficients end p-values were determined for three models. Model | contains all of the listed inde- pendent variables. Mode! Il excludes feroce-clamp time. Model I oxcludes cross-clamp time, age, and body sur- face area. Since there were too few observations in the lung surgery group {n= 7) for model |, only closed- and 'No significant difference between the groups (chi-square) Varabie Type of prophylaxis Cefazolin Ceftazidime + Other (63.8%) Vancomycin (25.1%) (11.2%) Sugeon 7 2 2 (617%) (272%) (25.1%) nae 60 yoarsold «60 years old (27.9%) (72.1%) Body Surface Area ——-<2.mt Bane (44.0%) (56.0%) Diabetes Present ‘Absent (32.2%) (67.8%) in Hospital 1 day >iday Beles sraeny ee) grams Surgery Type Lung Closed-Heat Open-Heart (127%) (72.7%) (96%) Gross-Clamp Time 60 minutes > 60 minutes (42.4%) (57.6%) Incidences of Postoperative Infection Baseline Phase | Phase It 3) (n=162) (n= 173) Cofazolin: 18% 35% 21% Ceftazidime + Vancomycin 10% 11% 24% open-heart surgeries were considered for the type of surgery variable. ‘The multivariate enalyocs that eval usted prophylactic regimen, other con- founding variables, and the need to change antibiotic regimen, regardiess of phase, found that antibiotics needed to be changed more often in the cefazolin (group compared with the ceftazidime plus vancomycin group (Table 4). High- risks of infection were also attributed to 2 specific surgeon, prasence of dia- betes, longer tength-of-stay before ‘surgery, and open-heart surgeries. ‘Goodness-offit assessments were made for models ll and Ill using the HosmerLemeshow statistic The sample of 323 patients were placed into 10 approximately equal groups ordered by tho patients’ predicted probebiies. Predicted probabiles of infection were ‘summed within groups, o obtain afited value, which wae compared with the observed number of infectons for that group. The resuils ofthe chi-square sta- {istic for both models (0.975 and 0.687) {ive no indication oflack-oF i DISCUSSION ‘These data show that there was no detectable difference in postoperative infection rates hetween the patients undergoing cardiothoracic surgeries iho received cefazolin or ceftazidime plus vancomycin by univariate analysis. ‘Although seven patients developed mediastinitis afr recelving cefazoin in phase I, this finding can be attributed to other variables. All seven patients had diabetes with elevated blood ghicose concentrations prior to surgery and their surgeries were performed by the sur- {goon associated with the highest rate of infection in model Multivariate analysis found a higher rato of antibiotic changes in the cofer olin group, for surgeon 1, for patients with diabetes, and for patients undergo- ing open-heart surgeries. It is possible that all of these variables could be associated with a higher rate of infec- tion, These exploratory data suggest that surgical technique is nearly as Important as the choice of antibiotic pro- phylaxis whon using chonge in ontibiot ic as @ surrogate marker for infection. ‘These data were useful in convincing the cardiothoracic surgeons at this fnst- tution to use cefazolin 2s the drug of ‘choice for cardiothoracic surgery pro- Phylaxis. The broad-spectrum antibiotic ‘group in this analysis did have a signif- ‘cantly longer stay in the ICU compared with the cefezolin group. Furthermore, the use of cefazolin alone is less exper- sive and could decrease the develop- ment of antibitic-resistant organisms. Hospital Pharmacy 383Antimicrobial Prophylaxis in Cardiothoracic Surgery Patients Variables Associated with a Higher Rate of Clinical Infection ‘Model (n= 203) oR Prophylaxis: Cefaz vs Ceft-V Other ve Conv Cefea vs Other 0.95 to 14.47 0.48 to 13.12 0.42 to 6.10 ‘Model (n= 323) (90% C) (00% c) oR 3.86 380" 099 1.84 10 10.45 1.17 10 13.38 0.40 to 2.64 ‘Model ih (n= 323) oR (20% cH) 4.6010 10.11 11310 12.49 0.42 to 266 Surgeon tvs3 2vs8 ive? BBR |aS8 4.11 t06.09 0:11 to 1.08 2.80 to 21.46 1.69 054 0.83 to 360 0.20 10 1.39 1143 to 7.81 0.82 to 352 0.20 to 1.35 1.44 to 757 Diabetes ‘Yoo va No & Days Before Surgery Vvs<1 ‘Surgery Type ‘Open vs Closed Heart 397° Cofaz = cefazolin Cof-V = ceftazidime-vancomycin OR = Odds Ratio 90% Cl = 90% confidence interval *p € 0.10, multiple logistic regression 1.58 ‘There is published evidence to suggest thal more targeted aid worse vative use of antibiotics can decrease the emergence of bacterial resistance. The use of broad-spectrum antimicro- bial prophylaxis may not adversely, affect the patient being treated; howev- er, it may increase the chances of a more serious, anlibiolicresistant infec- tion in a future patient, The increased tength-of-stay in phase Il and in the broad-spectrum antibiotic group could be related to more resistant infections from the previous use of the broad- spectrum regimen, The criteria for the use of antbi- tics for antimicrobial prophylaxis, established by the National Research Council Is based on whether surgeries are clean, cloan-contaminatod, eontam inated, or dry.” All of the cardiothoracic ‘surgeries in this study would be consid ‘ered clean. An important finding of the criginal NRC report was that there were 0.94 to 3.78 07710337 1.18.vs 13:70 1.92 40 4.49 1.07 103.79 1.1010 8.68, fewer infections in clean surgeries when santbiutic prupliylans wes used sparing ly. The infection rate was 9.4% with antibiotics and 2.9% without antibiotic. ‘Although the prolonged use of cefazoiin in this study could have mitigated this effect, this study did not show an increased rate of infection in the cof tazidime plus vancomycin, broad-spec- trum prophylaxis group of patients. There are limitations to this study. ‘Although this study included nearly 650 patients in the univariate analysis, it ‘would only have sutficient power (ie, 80% power) to detect a 7% diflerence in the infection rates between cefazolin ‘and ceftazidime plus vancomycin, assuming 2 10% incidence in ciinical Infection in the ceftazidime plus van- ‘comyoin group. Alco, tho obcorvational study design did not control for identi= ‘fed extraneous variables and the possi- bitty of other unidentifed confounding variables. 1.28 10 4.60 1.07 10 3.75 11310881 Mutivariate analysis did suggest Wat veflacidinne ples vancumyci required fewer antibiotic changes. The need to change antibiotics was based ‘only on the attending physicians’ impression that there was a need to improve the patient's care. It was not based on objective data (og, culture results). The prolonged use of “prophy- factic" antibiotics should also have an effect on the need to change antibiotics. Difierent results may be found if pro- phylaxis was used for 1 day. CONCLUSION This observational study found no ences in the rates of postoperative infection or diagnosed cases of medias tins or endocarditis In cardiothoracic ‘ourgory pationte givon cefazolin or cof- tazidime plus vancomycin for antimicro- bial prophylaxis. The results of a multi- variate exploratory analysis suggest that surgical technique, concomitant 384 Volume 37, April 2002diseases like diabetes, and type of surgery may be predictors of infection. Multivariate analysis also suggests that antibiotic therapy needs to be changed less offen when ceftazidime plus van- ‘comycin is used for prophylaxis. Since broad-spectrum antimicrobial prophylaxis may increase the develop- ment of resistant organisms and itis also more expensive, a broad-spectrum prophylaxis regimen could only be rec- ‘ommended if a randomized, controlled ‘rial proved that it is. more effective Because there are many confounders that could ater postoperative infection ralee and bosauco of tho low rato of postoperative infection in patients who receive cefazolin, such an experimental study would be very difficult to carry out These observational data, therefore, Antimicrobial Prophylaxis in Cardiothoracic Surgery Patients ‘support the continued use of cefazolin as the drug of choice for antibiotic pro- phylaxis in cardlothoracie surgeries. REFERENCES ween Agee puis Sen en ye 2. ASHP Commission on Therapeutics. ‘fe erp gittnee cn at obit prophylens ins in Pham, Rebstaes-o1as 3, Page CP, Bohnen JMA, Fletcher JR, et al. Antimicrobial prophylaxis for surg eal wounds, Surg. 4. Nana RE, Ziel 0. Anticrobil phone in coronary bypess ee ttical appraal DCP. 9orz6:476-84, 6. Kaiser AB. Antimicrobial prophylaxis feurgory, NN" Eng J) Mod. 1986;316:1129-28. ©, Hospital infection Control Practices Advisory Committee. Recommenda- {ions for preventing the spread of van- pricin resistance infect Conrel Hosp Epidemiol. 1995;16:105-13. 7. SAS Institute. SAS_ Tochnical Report_P-234 SASISTAT Software: ‘Tho GENMOD Procedure. Gary, NC: SAS Institute. 1999. 8, Agresti A, An Introduction to Cate- gical Data Anaysis, New York: Wiley: 98. Hosmer DW, Lemeshow S, Applied Logie Regression. New York: ley: 1o.National Academy of Sciences, National Research Council. Postopera- tive wound infections: The influence of Uultaviolet Iradiation of the operating room and of various other factors. Ann Surg. 1964; 160{suppl)32~135. n a Hospital Pharmacy 385