Antibiotics-Why So Many and When Should We Use Them?

By Dennis F. Bandyk

Antibiotic prophylaxis in vascular surgery has been proven beneficial to reduce surgical site infectionsafter reconstruction of the aorta, procedures on the leg that involve a groin incision, any procedurethat implants a vascular prosthesis or endoluminal stent, and lower extremity amputation forischemia. Bactericidal antibiotics administered before induction- cefazolin or cefuroxime for 1 to 2days alone or in combination with vancomycin if a hospital wound surveillance program indicates ahigh incidence of methicillin-resistant Staphylococcus aureus infection-is recommended. If a patientis felt to be at increased risk for infection and require prosthetic grafting, the use of a rifampin-soaked(1 mg/mL) gelatin- or collagen-impregnated graft may decrease the incidence of wound and graftinfection. Antibiotic treatment of established vascular graft infections should begin with broad­spectrum coverage for expected pathogens (S aureus, Staphylococcus epidermidis, Gram-negativebacteria) followed by culture-specific therapy based on antibiotic susceptibility testing. Specificantibiotic usage involves a decision regarding efficacy to expected or isolated pathogens versus itspotential side effects and the drug costs. New applications for antibiotics in vascular surgery includethe use of specific tetracyclines (doxycycline, azithromycin) as an inhibitor of matrix metalloprotein­ases to retard aortic aneurysm growth or for their antiinflammatory properties to retard atherogen­esis related to Chylamydia pneumoniae.Copyright 2002, Elsevier Science (USA). All rights reserved.

THE PREVENTION and treatment of microbialinfection are important aspects of clinical vas­

cular surgery. The vascular surgeon must be cogni­zant of preoperative, operative, and postoperativeprophylactic measures especially when a vascularprosthesis or endoluminal device is implanted. Therisk of developing an infection is determined by thedegree and virulence of microbial contamination aswell as the individual patient's host defenses to com­bat infection. As in other surgical disciplines, theclean wound infection rate after "open" vascularsurgery procedures should be 3% or less. Whenprocedures involve prosthetic graft usage, the inci­dence of graft infection is much less than postopera­tive wound infection rates and varies with graft im­plant site (aortoiliac, <1%; aortofemoral, <2%;femoropopliteal, <3%).1,2

Antibiotic therapy is important both for prophy­laxis and treatment of infectious complications aftervascular intervention, especially with the emergenceantibiotic-resistant bacterial strains. Methicillin-resis­tant Staphylococcus aureus (MRSA) has become acommon pathogen causing vascular infections-now

From the Division of Vascular and Endovascular Surgery,University of South Florida College of Medicine, Tampa, FL.

Address reprint requests to Dennis Bandyk, MD, Division ofVascular & Endovascular Surgery, Harbourside MedicalTower, Suite 650, 4 Columbia Dr, Tampa, FL 33606.

Copyright 2002, Elsevier Science (USA). All rights reserved.0895-796710211504-0008$35.0010doi:10.1053/svas.2oo2.36262

responsible for 20% to 25% of surgical site infec­tions, including patients undergoing lower limb am­putation for ischemia.3

,4 Although a comprehensivediscussion of antibiotic usage is beyond the scope ofthis article, the principles and recommendations citedin this review should impart guidance as to whenantibiotic therapy is indicated and what drugs shouldbe utilized initially.

Bactericidal antibiotics are preferable to bacte­riostatic antibiotics after vascular interventions,This is especially true for prophylaxis to preventprosthetic graft infection or when arterial recon­struction is required in an immune-compromisedpatient. Antibiotics with bactericidal properties andproven efficacy in vascular surgery have differingmodes of action to account for their antimicrobialactivity (Table 1).4 During therapy, microorgan­isms also can develop resistance to antibiotics inseveral ways including production of an enzyme(penicillinase or 13-lactamase; penicillin and ceph­alsporin resistance) to destroy the antibiotic ef­fects, development of a resistance factor (plas­mid-mediated change in cell surface receptor;vancomycin resistance), or spontaneous mutationof DNA gyrase (quinolone resistance). The devel­opment of 13-lactamase inhibitors (clavulanate, sul­bactam, tazobactam) used in combination with13-lactamase antibiotics reduces the likelihood ofdeveloping resistance during therapy.

Tissue concentration of the antibiotic is an im­portant determinant in preventing or controlling an

268 Seminars in Vascular Surgery, Vol 15, No 4 (December), 2002: pp 268-274

ANTIBIOTICUSAGE

Table 1. Mechanism of Action of Bactericidal Antibiotics Commonly Used in Vascular Surgery

269

Type of Antibiotic

{3-Lactams, penicillins, cephalosporins,carbapenems, monobactams

Vancomycin

QuinolonesAminoglycosideRifampinClindamycin

Mechanism of Action

Inhibitcell wall synthesis by interleukin with production or cross linking ofpeptidoglycans resulting in bursting effect from water influx into thebacterial cell.

Inhibits all wall synthesis by interfering with peptidoglycan production atsites different from penicillins and by inhibition of RNA synthesis

Interference with DNA replication and repairInhibition of protein synthesis by binding to 30S ribosomeBlocks RNA synthesis by inhibiting DNA dependent RNA polymeraseBinds to 50S ribosomes subunit and inhibits peptide bond formation

infection.6 Whereas serum concentrations are de­termined by route of administration, volume ofdistribution, and rates of metabolism or excretion,local concentration is highly dependent on tissuevascularity, lipid content of the tissue, and thedegree of protein binding of the drug. The ultimatechoice of an effective antibiotic involves decisionsregarding efficacy to expected or proven pathogensversus the potential side effects, toxicity, and costsof the drug. Adverse reactions including hypersen­sitivity and nephrotoxicity are of special concern invascular patients who often are elderly with mul­tiple comorbidities including diabetes and renalinsufficiency.

Vascular infections can be minimized if certainprinciples are followed.

• Avoid a prolonged preoperative hospital stayto minimize the development of skin floraresistant to commonly used antibiotics (ie,hospital-acquired strains).

• Have patients shower or scrub with an anti­bacterial soap the night before the operation.

• Control any remote infection before an elec­tive operation especially if a prosthetic graft orstent implantation is planned.

• Remove operative site hair immediately beforethe operation using clippers rather than a razorto minimize skin trauma.

• Protect vascular grafts from contact with anypotentially contaminating sources, especiallythe exposed skin adjacent to the operativefield, by the use of iodine-impregnated plasticdrapes or antibiotic-soaked towels.

• Avoid simultaneous gastrointestinal proce­dures during grafting procedures to preventgraft contamination with enteric organisms.

• Use preoperative prophylactic antibioticswhenever a prosthetic graft or stent is im­planted, for reconstructions of the abdominal

aorta, when the procedure involves a groinincision, and for lower limb amputation forischemia. Preoperative antibiotics also shouldbe considered when 2 or more patient-relatedrisk factors for surgical wound infection areidentified, including extremes of age, malnu­trition, chronic illnesses (diabetes, chronic ob­structive lung disease), remote infections, im­munosuppression, recent operations, or priorirradiation of the surgical site.

CLINICALUSE OF ANTIBIOTICS

Prophylaxis

Prophylaxis refers to the administration of anti­biotics before the occurrence of bacterial contam­ination, and the goal of therapy is to prevent thesubsequent development of infection. Of note, pro­phylactic antibiotics will not be effective when theprinciples of aseptic technique and wound manage­ment are not followed. Antibiotics should be ad­ministered systemically before incision of the skinand at regular intervals during the procedure tomaintain serum and tissue levels above the mini-

Table 2. Surgical Prophylaxis in Adults UndergoingProsthetic Graft/Patch Implantation During Clean

Procedures

• Cefazolin, 1-2 g intravenously slowly before induction ofanesthesia and repeated (1 to 2 g) every 8 hours for 24 to48 hours, or cefuroxime, 1.5 g intravenously and every 12hours for total of 6 g.

• When methicillin-resistant S aureus (MRSA) is cultured onbody surfaces or is a known important pathogen inhospitalized patients, add vancomycin, 1 g intravenouslyinfused over 1 hour.

• If patient has a cephalosporin allergy, give aztreonam 1 gintravenously every 8 hours for 24 hours.

• If patient has a vancomycin allergy, give clindamycin, 900mg intravenously over 20 to 30 minutes followed by 450

to 900 mg intravenously every 8 hours for 24 hours.

270

mal bactericidal concentration for expected patho­gens (Table 2).7 Expected pathogens in vascularoperations are S aureus, Staphylococcus epidermi­dis, diphtheriods, and Gram-negative enterics.When a hospital surveillance program shows ahigh incidence of MRSA infection, prophylaxisalso should include vancomycin therapy.8 Addi­tional dosing may be needed during the operationbased on the elimination and volume of distribu­tion of the antibiotic, with higher or more frequentdoses necessary in patients with prolonged proce­dures (>4 hours) or excessive changes in bloodvolume, fluid administration, or renal blood flowduring the procedure. Culture-specific antibioticsshould be prescribed for patients undergoing vas­cular graft implantation who have coexisting infec­tions of the leg/foot, ie, diabetic foot infection, orat other remote sites (pneumonia, urinary tractinfection, endocarditis). Extending antibiotic ad­ministration beyond 2 days does not increase effi­cacy although at some vascular centers, prophylac­tic antibiotics are continued for 3 to 5 days inpatients deemed to be at high risk for infectionfrom bacteremia, prolonged preprocedure hospital­ization, or high (> 10%) institutional wound infec­tion rates. There is no evidence to support continu­ing antibiotic prophylaxis until central venous orFoley bladder catheters are removed.

Appropriate use of prophylactic antibiotics hasbeen shown to reduce infectious morbidity, espe­cially wound infection, and its associated hospitalcosts after vascular surgery.9-1 I In 1978, Kaiser eta19 documented the efficacy of cefazolin to preventsurgical site infection when compared with pla­cebo (0.9% v 6.8%; P < .01). The difference inwound infection was attributable to the preventionof infection by cefazolin-sensitive bacteria strains,whereas the incidence of cefazolin-resistant strainswas similar in both regimens. Using current-dayrecommended antibiotic prophylaxis, wound infec­tion rates of 1 to 4% after open arterial reconstruc­tions (aortic aneurysm repair, < 1%, aortofemoralbypass, 3%, lower limb bypass, 4%) can be ex­pected.

Early graft infections usually are the result ofwound sepsis, reoperation for hematoma, concom­itant remote infection, and impaired immunocom­petence. Patients who have late-appearing graftinfections often have a history of multiple opera­tions for graft thrombosis or false aneurysm. Staph­ylococci, especially coagulase-negative staphylo-

DENNIS F. BANDYK

cocci, are the primary opportunists that colonizevascular grafts, and in the clinical circumstances ofinjured perigraft tissues, altered immune functionassociated with malignancy, leukopenia, lympho­proliferative disorders, or drug administration (eg,steroids or chemotherapy) can cause graft infectiondespite low numbers of contaminating bacteria.Topical antibiotics including soaking the vascularprosthesis in a rifampin solution (1 mg/mL) hasbeen shown to reduce the incidence of groin infec­tion after aortofemoral bypass grafting. In a ran­domized clinical trial of 2,522 patients, use of arifampin-soaked, gelatin-impregnated polyesteraortofemoral graft reduced groin wound infectionrates (4.4% v 2.7%, control: P < .05), but subse­quent graft infection rates were similar (0.6% v0.3%, controls).ll All graft infections were causedby S aureus.

After prosthetic graft implantation, patientsshould be fully informed of the potential risk oflate graft colonization and infection via bactere­mia, especially after interventional proceduressuch as dental work, colonoscopy, and cystoscopy.Antibiotic prophylaxis is recommended in theseinstances (amoxacillin, 2 g orally 1 hour before theprocedure or if a pencillin allergy is present, clin­damycin, 500 mg orally 1 hour before the proce­dure).

Therapeutic Use

The basic principles of antibiotic therapy forsurgical infections should be followed when treat­ing a suspected or documented vascular graft in­fection (Table 3). Essential to antibiotic therapy isknowledge of antibiotic efficacy, drug interactions,and whether the bactericidal properties of the drugare concentration independent or concentration de­pendent. In general, aminoglycoside antibiotics

Table 3. Principles of Antibiotic Therapy

• The organism should be sensitive to the antibiotic basedon susceptibility testing.

• Choose a bactericidal antibiotic, and use synergistictherapy when appropriate, ie, Pseudomonas, enterococcal,

and S epidermidis infections.• Choose the most narrow-spectrum antibiotic to minimize

superinfection.

• Antibiotic should be administered in doses that ensureadequate peak concentrations and tissue penetration.

• Frequency of administration is based on the half-life andthe route of elimination of the antibiotic.

• Ensure proper duration of therapy.

ANTIBIOTICUSAGE

(gentamicin, tobramicin, amikacin) are noted forhaving concentration-dependent killing, and mon­itoring of serum levels for efficacy and toxicity isrecommended. In seriously ill patients, markedvariability in pharmacodynamics, eg, volume ofdistribution and clearance) of antibiotic has beenshown. Once-a-day dosing is possible in thesepatients because of the altered pharmcodynamicsand a prolonged postantibiotic effect (PAE). Ami­noglycoside therapy is associated with long PAE­the ability to suppress bacterial growth despiteserum concentrations below the minimum inhibi­tory concentration (MIC) of the bacteria strainbeing treated. By comparison, 13-lactam antibioticsexhibit concentration-independent bacterial kill­ing, and the length of time serum levels remainabove the MIC, rather than the peak concentration,is important for efficacy. Thus, frequent dosingintervals at lower doses or continuous infusion of13-lactams are useful to ensure that serum concen­tration remain above the MIC for prolonged peri­ods.

The majority (>80%) of graft infections arediagnosed more than 4 months after graft implan­tation (aortic graft infection, mean of 42 ::!:: 28months; lower limb graft infection, mean of 7 ::!:: 4months). 12 As indicated above, early «4 months)graft infection generally is caused by S aureus orGram-negative bacteria and frequently originatesfrom a failure of primary wound healing. Thepresence of hematoma, lymphatic fistula, and de­vitalized dermis increase the risk for graft infectionand should be treated aggressively wound explo­ration, debridement, and primary wound closure.

If a surgical site infection develops and involvesan underlying subcutaneous graft segment (ie,groin, limb, neck), inspection and physical exam­ination will identify cellulitis, a wound with puru­lent drainage, or inflammatory perigraft mass, oranastomotic aneurysm. Petechial lesions of thelower limb skin can indicate septic emboli. Bycomparison, late-appearing (>4 months) graft in­fections typically present without sepsis but ratherclinical signs of an indolent infection (eg, falseaneurysm formation, cutaneous sinus tract orperi­graft inflammation without evidence of graft incor­poration). Most late graft infections are causedby S epidermidis. If the presentation of a lategraft infection involves Gram-negative bacteremia,graft-enteric erosion should be suspected. Methi­cillin-resistant S aureus (MRSA) now accounts for

271

one quarter of late prosthetic graft infections. Ac­cordingly, treatment with vancomycin alwaysshould be included in the initial antibiotic regi­men. 12

Identification of the infecting organisms is nec­essary to confirm the diagnosis of graft infectionand to select appropriate antibiotic therapy. Peri­graft fluid or tissue cultures are adequate in pa­tients with invasive graft infections associated withfever and leukocytosis. Virulent organisms, suchas S aureus, streptococci, and Gram-negative bac­teria typically are isolated. More sensitive micro­biologic techniques should be used to identify thecausative organism when a biofilm infection ispresent as evident by Gram's stain of perigraft pusshowing only white blood cells but no organisms.Mechanical disruption of the bacteria from graftsurface by tissue grinding or ultrasonic disruptionfollowed by culture in broth media enhances bac­terial recovery. Such microbiologic techniques arecritical to recover coagulase-negative staphylo­cocci, such as S epidermidis, that reside in lownumbers within the graft material as a biofilminfection.

When possible, pathogen(s) should be identifiedbefore operation, permitting bactericidal-level an­tibiotics to be administered pre- and postopera­tively. If the infecting organism has not beenisolated, broad-spectrum antibiotics, ie, an amino­glycoside plus semisynthetic penicillin, a second­generation cephalosporin, or ampicillin plus sul­bactam should be given. When S aureus or Sepidermidis is the most likely pathogen, parenteraltherapy with a first- or second-generation cephalo­sporin and vancomycin are appropriate. Once op­erative cultures have isolated all infecting organ­isms, antibiotic coverage should be modified basedon antibiotic susceptibility testing of the recoveredstrains. The duration of antibiotic administrationafter treatment by graft excision is empiric, but atleast 4 weeks of systemic antibiotics is recom­mended. After in situ prosthetic replacement orprosthetic graft preservation procedures long-termantibiotic (parenteral antibiotics for 6 weeks, fol­lowed by oral antibiotics for 3 to 6 months) isrecommended. Oral antibiotic treatment of MRSAinfections is now possible using Iinezolid, 600 mgorally every 12 hours. 13 The incidences of recur­rent infection and aortic stump sepsis may bedecreased with long-term or lifelong antibiotic ad-

272

ministration, especially in the presence of positivearterial wall cultures. 14

Antibiotic therapy should be viewed as an ad­junct to the treatment of a vascular site infection.Surgical management of the infection site by ab­scess drainage, debridement of devitalized tissue,and excision of the infected graft is essential. Inselected patients, with exposed grafts but no in­volvement of anastomotic site, preservation of thegraft with serial surgical wound debridement, cou­pled with antibiotic therapy and muscle flap cov­erage, may be possible in selected patients. Repeatwound cultures should be performed if stagedprocedures are used to identify any development ofbacterial resistance or change in the microbialflora. Patients with virulent graft infections mayrequire immune and nutritional support, in additionto antibiotic therapy, for successful resolution ofthe infectious process.

Diabetic Foot Infection

Vascular surgeons frequently are involved in themanagement of diabetic foot infection, especiallywhen the condition is associated with atheroscle­rosis obliterans. Chronic, recurrent, limb-threaten­ing infections typically are polymicrobial, includ­ing aerobic cocci, Gram-negative bacilli, andanaerobes. Cultures of the ulcer are unreliable, andprompt surgical exploration for abscess drainage,deep wound culture, and debridement for necrotiz­ing soft tissue infection or fascitis is necessary. Theability to insert a probe to the bone in a diabetic'sfoot involved by infection suggests concomitantosteomyelitis. Broad-spectrum antibiotic therapybased on the extent and severity of foot infection isrecommended (Table 4). The antibiotic regimen

DENNIS F. BANDYK

always should include an agent bactericidal tostaphylococci and streptococci. For limb-threaten­ing infections, vancomycin is recommended forempiric treatment of possible MRSA colonization.Prognosis depends on blood supply, and immediateassessment of ankle and toe pressure is recom­mended in patients with absent pedal pulses. Anabsolute ankle systolic pressure less than 70 mmHg or toe pressure less than 40 mm Hg shouldprompt additional arterial testing (duplex ultra­sound scan, magnetic resonance angiography, orcontrast angiography) to determine the nature andextent of occlusive disease. Arterial bypass graft­ing to restore normal foot perfusion should beperformed as soon as the foot infection is con­trolled. The duration of antibiotic therapy has notbeen well studied. For soft tissue infections with­out osteomyelitis, a 1- to 2-week course is effec­tive; whereas for limb-threatening infections 2weeks or longer therapy is recommended. In gen­eral, antibiotic therapy can be discontinued whenall signs of infections have resolved, even thoughthe wound has not completely healed.

OTHER VASCULAR INFECTIONS

Empiric treatment for a suspected vascular in­fection is, on occasion, indicated. When culture ofabdominal aorta aneurysm thrombus or graft asso­ciated with anastomotic pseudoaneurysm isolatesbacteria, typically S epidermidis or on occasion aCandida sp., antibiotic treatment is recommended.In the absence of clinical signs of infection, 7 to 10days of parenteral antibiotics (vancomycin, Diflu­can) followed by 4 to 6 weeks of oral therapy issufficient.

Extent of Infection

Previously untreated, withoutosteomyelitis

Chronic, recurrent, or limb

threatening

Septic, advanced infectionwith subcutaneous air

Table 4. Antibiotic Therapy for Diabetic Foot Infection

Antibiotic Therapy Options

Ampicillin/sulbactam (Unasynl. 3 9 intravenously every 6 hours, c1indamycin (Cleocin 450

to 900 mg intravenously every 8 hoursOr, levofloxacin (Levaquinl. 750 mg intravenously/orally ever day :t clindamycin, 450 to

900 mg intravenously every 8 hours.Pipercillinltazobactam (Zosynl, 3.375 9 intravenously every 6 hours or 4.5 9 intravenously

every 8 hours, or, ticarcillin/clavulanate (Timentin), 3.1 9 intravenously every 6 hours, or,cefoxitin, 2 9 intravenously every 8 hours + metronidazole (Flagyll, 1 9 intravenouslyevery 12 hours, or, ciprofloxin (Cipro), 400 mg intravenously every 12 hours +c1indamycin, 450 to 900 mg intravenously every 8 hours.

Imipenum cilastatin (Primaxin), 0.5 9 intravenously every 6 hours + vancomycin, 1 9intravenously every 12, or, meropenum (Merem), 1 9 intravenously every 6 hours +vancomycin, 1 9 intravenously every 12 hours.

Adapted from the 32nd Edition of The Sanford Guide to Antimicrobial Therapy.'

ANTIBIOTICUSAGE

NONINFECTIOUS USES OF ANTIBIOTICS

Atherosclerosis and aneurysmal degenerationare mutifactorial processes leading to vessel dis­ease and loss of function. Chlamydia pneumoniae(CPn), a Gram-negative, obligate, intracellularpathogen, has been suggested to play a role inatherogenesis by inducing chronic inflammationthat contributes to artery wall damage. CPn canmaintain a low-grade infection in human endothe­lial cells and results in expression of endothelialdysfunction or specific proteases that degradestructural proteins that leads to aneurysm forma­tion. Experimental and clinical studies have shownthat treatment with protease inhibitors such as atetracycline (doxycycline) or macrolide antibiotic(azithromycin) will decrease inflammation and re­tard development of arteriallesions. 15.16 In a recentprospective, randomized clinical trial, azithromy­cin (500 mg/wk) improved endothelial cell func­tion in a study population of patients with knowncoronary artery disease and positive CPn-IgG an­tibody titers. 16 CPn infection also promotes plaqueinflammation and its thrombogenic potential. Itstreatment prevents CPn-induced aortic intimalthickening in animal models,17 and further study inappropriate patient populations is underway basedon the clinical observation that patients with acutecoronary syndromes who received antibiotic treat­ment during their hospitalization have a significantreduction in subsequent cardiac events. 16

The administration of doxycycline (150 mg/d)has been shown to decrease the growth rate of"small" abdominal aortic aneurysms. 18 A higher(P < .03) rate of AAA expansion was observed in

273

patients in the placebo group with elevated CPnIgG antibody titers. Doxycycline treatment had noeffect on antibody titers, but C-reactive proteinlevels were significantly lower at the 6-monthfollow-up. The benefit of doxycycline administra­tion also may be because of its inhibition of matrixmetalloproteinases, the expression of which areincreased in patients with AAA and contribute tostructural wall protein degradation. Based on thesepilot study data, multicenter, prospective clinicaltrials currently are being planned for patients withsmall AAAs or after endoluminal repair whenAAA size does not decrease. Because doxycyclinetherapy is well tolerated, it is reasonable to con­sidered treatment of patients with AAAs who de­cide against repair or are judged not to be candi­dates for repair.

SUMMARY

A sound understanding of vascular infectionsand the concepts of antibiotic prophylaxis are im­portant for safe and effective antibiotic usage.Vascular surgeons should develop practice patternsusing antibiotics based on evidence-based studiesthat indicate efficacy. This review provides guide­lines for initial antibiotic administration for pro­phylaxis during arterial reconstructive procedures,treatment of vascular graft infections, and manage­ment of diabetic foot infections. Noninfectiousapplications for antibiotics are a new and excitingadvance in vascular surgery and may have a role inimproving the success of stent angioplasty and thetreatment of abdominal aortic aneurysm disease.

REFERENCES

I. Edwards WH, Martin RS III, Jenkins JM, et al: Primarygraft infections. J Vasc Surg 6:235-239, 1987

2. Bandyk DF: Vascular graft infections: Epidemiology, mi­crobiology, pathogenesis and prevention, in Bernhard VM,Towne JB (eds): Complications in Vascular Surgery, St Louis,MO, Quality Medical Publishing, 1991, pp 223-234

3. Jones ME, Schmitz FJ, Fluit AC, et al: and the SENTRYParticipants Group: Frequency of occurrence and antimicrobialsusceptibility of bacterial pathogens associated with skin and softtissue infections during 1997 from an international surveillanceprogram. Eur J Clin Microbiollnfect Dis 18:403-408, 1999

4. Grimble SA, Magee TR, Galland RB: Methicillin resistantStaphylococcus aureus in patients undergoing major amputa­tion. Eur J Vasc Endovasc Surg 22:215-218, 2001

5. Durham RM, Mazuski JE: Surgical infection: Principlesof management and antibiotic usage, in Miller TA (ed): Modern

Surgical Care (ed. 2), St Louis, MO, Quality Medical Publish­ing, 1998, pp 149-172

6. Fry DE, Pitcher DE: Antibiotic pharmacokinetics in sur­gery. Arch Surg 125:1490-1495, 1990

7. Gilbert DN, Moellering RC Jr, Sande MA: The SanfordGuide to Antimicrobial Therapy (ed 32), Hyde Park, VT,Antimicrobial Therapy, 2002, p 116

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9. Kaiser AB, Clayson KR, Mulherin JL Jr, et al: Antibioticprophylaxis in vascular surgery Ann Surg 188:283-289, 1978

10. Edwards WH Jr, Kaiser AB, Tapper S, et al: Cefaman­dole versus cefazolin in vascular surgical wound infectionprophylaxis: cost effectiveness and risk factors. J Vasc Surg18:470-476, 1993

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II. Koskas F, Goeau-Brissoniere 0, Pechere JC: Preventionof early wound and graft infection with rifampicin-bondedknitted polyester-grafts: Results of the rifampicin bonded graftsEuropean trial (RBGET). Rifampicin Bonded Graft EuropeanTrial, Paris 12-13 May, 1995

12. Bandyk DF, Novotney ML, Back MR, et al: Expandedapplication of in situ replacement for prosthetic graft infection.J Vasc Surg 34:411, 2001

13. Wilson SE: Clinical trial results with linezolid, an ox­azolidinone, in the treatment of soft tissue and postoperativegram-positive infections. Surg Infect 2:25-35, 200 I

14. Lalka SG, Malone JM, Fisher DF Jr, et al: Efficacy ofprophylactic antibiotics in vascular surgery: An arterial wallmicrobiologic and pharmacokinetic perspective. J Vasc Surg10: 108-114, 1989

15. Petrinec D, Liao S, Holmes DR, et al: doxycycline

DENNIS F. BANDYK

inhibition of aneurysmal degeneration in an elastase-induce ratmodel of abdominal aortic aneurysm: Preservation of aorticelastin associated with suppressed production of 92 kD gelati­nase. J Vasc Surg 23:336-346, 1996

16. Parchure N, Zouridakis EG, Kaski JC: Effect of azithro­mycin treatment on endothelial function in patients with coro­nary artery disease and evidence of Chlamydia pneumoniaeinfection. Circulation 105: 1298-1303, 2002

17. Muhlestein lB, Anderson JL, Hammond EH, et al: In­fection with Chlamydia pneumoniae accelerates the develop­ment of atherosclerosis and treatment with azithromycin pre­vents it in a rabbit model. Circulation 97:633-636, 1998

18. Mosorin M, Juvonen J, Biancari F, et al: Use of doxy­cycline to decrease the growth rate of abdominal aortic aneu­rysms: A randomized, double-blind, placebo-controlled pilotstudy. J Vasc Surg 34:606-610, 2001