Sử dụng kháng sinh pps

In 1970, Buchholz and Engelbrecht1introduced the concept of impreg-nating acrylic bone cement with antibiotic as a possible means of preventing infection in patients undergoing total joi

In 1970, Buchholz and Engelbrecht1

introduced the concept of

impreg-nating acrylic bone cement with

antibiotic as a possible means of

preventing infection in patients

undergoing total joint arthroplasty

Since then, antibiotic-impregnated

cement has become more commonly

used for revision total joint

arthro-plasty and, as antibiotic-impregnated

cement spacers or beads, for

treat-ment of infection during two-stage

revision arthroplasty than it has for

infection prophylaxis in primary

total joint arthroplasty Even

with-out the contribution of

antibiotic-impregnated cement, the infection

rate after standard primary total

joint arthroplasty in modern

oper-ating rooms has been reduced to

between 0.3% and 2% A survey

from 1995 concerning orthopaedic

operating room practices and

equip-ment suggested that this reduction

has been achieved by the access to

laminar airflow (present in 49% of hospital operating rooms), body exhaust suits (in 69%), high airflow (in 85%), and ultraviolet lights (in 14%).2 Reported infection rates after revision total joint arthroplasty vary widely because of the large number

of patient variables

Several types of acrylic bone cement in current use incorporate antibiotics, either premixed by the manufacturer or added by the sur-geon in the operating room In the United States, commonly used cements such as Palacos (Smith &

Nephew, Memphis, TN), Simplex (Howmedica, Rutherford, NJ), CMW (DePuy, Warsaw, IN), and Zimmer (Zimmer, Warsaw, IN) are mixed with antibiotics by the sur-geon Commercially prepared ad-mixtures such as AKZ (Simplex P with colistin and erythromycin), Refobacin-Palacos R (Palacos R with gentamicin cement), and Septopal

(beads of Palacos R with genta-micin) are not currently available in the United States Some hospital pharmacies (2.2%) prepackage ce-ment with antibiotic for later use in the operating room.3

A survey of 1,015 orthopaedic surgeons in the continental United States revealed that 56% have im-pregnated their bone cement with antibiotic for at least some cases.2

Surgeons specializing in joint recon-struction were more likely to use antibiotic in bone cement (88%) Sixty-five percent of all surgeons surveyed reported that they

adjust-ed antibiotic usage according to microbial sensitivity; of this group, 70% used tobramycin; 26%, genta-micin; 18%, vancomycin; 15%, cephalosporins; and 3%, combined antibiotics Antibiotics in liquid

Dr Joseph is resident, Department of Ortho-paedic Surgery, Musculoskeletal Research Center, NYU–Hospital for Joint Diseases, New York, NY Dr Chen is resident, Department of Orthopaedic Surgery, Musculoskeletal Research Center, NYU–Hospital for Joint Diseases, New York Dr Di Cesare is Associate Professor of Orthopaedic Surgery, Department of Ortho-paedic Surgery, Musculoskeletal Research Center, NYU–Hospital for Joint Diseases, New York.

Reprint requests: Dr Di Cesare, 15th Floor,

301 East 17th Street, New York, NY 10003 Copyright 2003 by the American Academy of Orthopaedic Surgeons.

Abstract

The use of antibiotic-impregnated cement in revision of total hip arthroplasty

pro-cedures is widespread, and a substantial body of evidence demonstrates its

effi-cacy in infection prevention and treatment However, it is not clear that

it is necessary or desirable as a routine means of prophylaxis in primary total

joint arthroplasty In the management of infected implant sites,

antibiotic-impregnated cement used in one-stage exchange arthroplasties has lowered

rein-fection rates In two-stage procedures, use of beads and either articulating or

nonarticulating antibiotic-impregnated cement spacers also has lowered

reinfec-tion rates In addireinfec-tion, spacers reduce “dead space,” help stabilize the limb, and

facilitate reimplantation Problems associated with antibiotic-impregnated

cement in total joint arthroplasty include weakening of the cement and the

genera-tion of antibiotic-resistant bacteria in infected implant sites.

J Am Acad Orthop Surg 2003;11:38-47

in Total Joint Arthroplasty

Thomas N Joseph, MD, Andrew L Chen, MD, and Paul E Di Cesare, MD

form, generally considered to be

less desirable than the powdered

form (because of the effects to

cement polymerization), were used

by as many as 11% of the surgeons

surveyed, possibly because of the

general unavailability of a

pow-dered form of gentamicin in the

United States In performing

prima-ry arthroplasties, approximately

12% of surgeons always used

anti-biotic-impregnated cement, 69%

never used it, and 19% used it

some-times Of those who did use it, 68%

did so in less than one third of their

aseptic revision total joint

arthro-plasties However, over 80% used it

more than two thirds of the time in

septic revision total joint

arthroplas-ty Over half often used

antibiotic-impregnated cement beads in

two-stage reimplantation for infections;

32% often used

antibiotic-impreg-nated cement spacers in hips; and

69% often used such spacers in

knees Of those using

antibiotic-impregnated cement, 28% used a

single-stage reimplantation in total

joint arthroplasty infection, while

72% used a two-stage approach.2

These data suggest that no

com-monly accepted standard exists

regarding the use of

antibiotic-impregnated cement in orthopaedic

surgery

The FDA takes no official

posi-tion on the use of antibiotics in

cement A document issued July 17,

2002, requires that cement labeling

contain the warning, “PMMA bone

cement is contraindicated in the

presence of active or incompletely

treated infection, at the site where

the bone cement is to be applied.”4

Laboratory Studies

A number of criteria must be met

for antibiotics to be effective when

mixed with methylmethacrylate

The preparation must be sufficiently

thermally stable to withstand the

heat of polymerization The

antibi-otic must not be adversely affected

by body temperature and must be water soluble so that it can diffuse into surrounding tissues The antibiotic must have a bactericidal effect at the tissue levels attained;

furthermore, it must be released gradually over an appropriate time period The preparation must evoke minimal local inflammatory

or allergic reaction Development of resistance should be rare to nonexis-tent; common pathogens must be

considered, including Staphylococcus

aureus, S epidermidis, coliform, and

others, such as anaerobes Finally, the antibiotic must not significantly compromise mechanical integrity, especially if the cement is used for implant fixation

In vitro analyses of antibiotic elu-tion and mechanical stability have been done with a variety of antibiot-ic-cement combinations The stable incorporation of aminoglycoside antibiotics (eg, gentamicin and tobramycin) into cement and their elution therefrom are well estab-lished Vancomycin is gaining pop-ularity because of its effectiveness against methicillin-resistant bacteria

as well as its general availability

Although penicillins and cephalo-sporins exhibit adequate elution and stability, they are often avoided be-cause of their potential allergenicity

In one study, in vitro testing of van-comycin- and tobramycin-impreg-nated cement demonstrated elution

of antibiotic for the entire 9-week study period; the highest elution rate occurred at 18 hours (between 3 and 5 times the rate that occurred at

72 hours).5 Ciprofloxacin, a more re-cent addition to bone cement, may gain in popularity because of its wide antibiotic spectrum and

gener-al availability Ciprofloxacin elution met or exceeded the minimum inhibitory concentration for com-mon organisms associated with osteomyelitis for up to 42 days.6

Recent studies7,8 indicate that ciprofloxacin may inhibit bone,

liga-ment, and soft-tissue healing; this is

a concern, particularly in total knee revision surgery

Lipids may impede the leaching process from cement The peptide antibiotics vancomycin and poly-myxin B nonapeptide have been shown to elute for a longer period than do the nonpeptide antibiotics gentamicin, novobiocin, and eryth-romycin.9 Molecular weight also appears to play a role One in vitro study indicated that vancomycin is eluted 10 times less efficiently than tobramycin from antibiotic-impreg-nated cement, probably because of its higher molecular weight.10 Other

in vitro studies, however, found no marked difference between the two.11

Palacos cement appears to pro-vide the best elution profile for most antibiotics A study of the elution characteristics of Palacos and CMW acrylic cements showed that CMW 1 released 24% less tobramycin and 36% less vancomycin than did Pala-cos; CMW 3 released 34% less tobra-mycin and 38% less vancotobra-mycin.5

Another in vitro study, in which Palacos and Simplex beads and spacers were impregnated with 4 g

of either vancomycin or tobramycin

in 40 g of cement, also showed antibiotic eluting from Palacos at higher levels.12 Concentrations re-mained above the minimum

inhibi-tory concentration for S aureus

longer in Palacos than in Simplex

In another study, elution of van-comycin, daptomycin, and amikacin from Palacos exceeded that of Simplex, Zimmer Dough-Type, and Zimmer LVC.13

Commercially prepared

antibiot-ic cement may be superior to intra-operatively mixed cement Elution

of gentamicin and tobramycin from laboratory-customized Zimmer, Simplex, or Palacos beads compared with elution from commercially pre-pared gentamicin-PMMA (Septopal) beads showed that more total an-tibiotic was eluted from the latter, and was maintained at higher

con-centrations, than it was in the beads

to which antibiotics were added by

the investigators.14

The results of studies of the effect

on elution of combinations of

antibi-otics, typically vancomycin and

tobramycin, are inconclusive In one

study, elution of vancomycin was

minimally affected by tobramycin,

while elution of tobramycin was

reduced by vancomycin.10 In

anoth-er study, the elution rate of

tobramy-cin increased by 68% and that of

van-comycin by 103% when these

antibi-otics were combined.15 In the first

study,10vacuum-mixed Simplex was

used, and in the second,15

nonvacu-um-mixed Palacos In both, the most

advanced means of measuring

an-tibiotic were used An in vivo study

using the prosthesis of

antibiotic-loaded acrylic cement

(PROSTA-LAC; Smith & Nephew, Memphis,

TN) demonstrated a statistically

sig-nificant (P = 0.011) increase in the

elution of vancomycin when the

dose of tobramycin was increased

from 2.4 to 3.6 g per dose of cement;

Simplex was used in 12 patients and

Palacos in 37.16 The investigators

changed the cement early in their

study after finding evidence in the

literature suggesting better antibiotic

elution from Palacos

Klekamp et al10demonstrated that

compressive and fatigue strength

decreased with the addition of

van-comycin or tobramycin to cement

Cement impregnated with 1, 2, or 3

g of vancomycin failed at 90%, 70%,

and 50%, respectively, of the

num-ber of cycles to failure for

antibiotic-free cement Likewise, cement with

1.2 and 2.4 g of tobramycin failed at

80% and 60%, respectively, of the

number of cycles to failure for

con-trols Although fatigue strength

data were statistically significant (P

< 0.05), the results of compressive

strength tests demonstrated a

de-creasing trend yet were not

statisti-cally significant Routinely used

lyophilized vancomycin was found

to greatly reduce cement fatigue

strength The authors suggested using vancomycin P (an ultrafine powder) in bone cement intended for prosthesis fixation because it has less detrimental effect on cement strength Askew et al17 found that the addition of 1 g of either tobra-mycin or vancotobra-mycin resulted in nominal bending strength reduc-tions (6% and 1%, respectively, compared with controls) Another study confirmed that the addition of 1.2 g of tobramycin to 40 g of Sim-plex powder did not significantly de-crease fatigue strength.18 Vancomy-cin L (lyophilized) should be finely ground when used for prosthesis fixation to prevent mechanical weakening; however, large crystals should not be completely pulver-ized when preparing beads or spac-ers because the crystals facilitate antibiotic elution

Morita and Aritomi19showed no reduction in tension and bending strengths of cefuzonam-impregnated cement when <3 g was used Earlier studies showed similar results with respect to compressive and tension strengths of cement impregnated with gentamicin, oxacillin, and cefa-zolin.20 Addition of more than 4.5 g

of gentamicin has been shown to

substantially weaken cement to a level below that appropriate for implant fixation.21 Reduction of no more than 10% in bone cement strength is considered acceptable for use in total joint arthroplasty fixa-tion; however, weaker antibiotic-impregnated cement may be used in beads and spacers Table 1 lists ap-propriate doses of antibiotic im-pregnation in cement for prosthesis fixation and for spacers and beads Vacuum mixing, which reduces the number of voids in bone ce-ment, improves the mechanical properties of antibiotic-impregnated cement When cylindrical cement-vancomycin specimens were sub-jected to fatigue testing (uniaxial mode), cycles to failure were 15% to 58% greater in vacuum-mixed speci-mens than in those mixed at atmos-pheric pressure Fracture of antibi-otic-impregnated cement specimens during cyclic testing was reduced

up to tenfold with vacuum mixing

or with vigorous pulverizing of the antibiotic before mixing.10 Another study showed vacuum mixing also reduced fivefold the radiograph-ically apparent porosity of antibiotic-impregnated cement specimens but may inhibit antibiotic release.17 In

Table 1 Reported Doses * of Antibiotics Used in Antibiotic-Impregnated Cement 13,26,44,53-55

Antibiotic Dose for Prosthesis Fixation Dose for Spacers and Beads

Ticarcillin Not appropriate 5 to 13 g

Vancomycin 1 g (vancomycin P) 3 to 9 g (vancomycin P or L)

* Per 40-g batch of cement

P = ultrafine powder, L = lyophilized, NR = not reported in the literature

one study, vancomycin

vacuum-mixed with Simplex (1:40 ratio)

released slightly less than half the

antibiotic that air-mixed cement did;

no antibiotic release was detectable

after 48 hours.13 Another study,

however, found adequate

antibacte-rial activity lasting for 21 days.17

Dextran has been used to

en-hance porosity and thus improve the

elution of antibiotic One

prepara-tion with dextran released

approxi-mately 4 times as much antibiotic as

did a dextran-free preparation, and

elution remained detectable for 10

days versus 7 days, respectively.13

However, dextran degrades the

mechanical properties of cement;

therefore, its use for prosthetic

fixa-tion should be extremely limited

Centrifugation, another preparation

technique, markedly increased the

fatigue life of Simplex both with and

without tobramycin by a factor of

eight

Increase in the surface area of

antibiotic-impregnated cement

spac-ers has been shown to increase

elu-tion of antibiotic in vitro Holtom et

al22 demonstrated that fenestrated

spacers with a 40% greater surface

area resulted in a 20% higher elution

rate of vancomycin from Palacos

ce-ment than from standard or

donut-shaped spacers Masri et al23

demon-strated a significant (P = 0.05)

in-crease in the elution of tobramycin

over 1 week with the use of Simplex-impregnated blocks that had a 9%

increased surface area-to-volume ratio

Antibiotics in liquid form mixed with cement dilute the catalyst that

is needed for the cement curing process, thereby adversely affecting both the curing time and final mechanical properties of cement;

accordingly, they are not recom-mended Table 2 lists antibiotics that can be mixed with cement

In Vivo Studies

The penetration of antibiotics re-leased from antibiotic-impregnated cement into surrounding tissues has been evaluated in both animal and human studies Concentrations of antibiotic in hematoma, granulation tissue, and bone vary according to antibiotic Local concentrations, however, have been found to be consistently higher than serum con-centrations and usually exceed the minimum inhibitory concentrations for target pathogens

The elution of several antibiotics from Simplex cement was measured

in samples from dogs over a 28-day period.24 Clindamycin, vancomy-cin, and tobramycin exhibited elu-tion characteristics that reached con-sistently high levels in bone and

granulation tissue Cefazolin and ciprofloxacin were maintained at high concentrations in granulation tissue but at low levels in seroma and bone Ticarcillin showed unfa-vorable elution characteristics in granulation tissue, seroma, and bone

Experimentally produced para-spinal wounds (fractured, infected spinous processes) in rabbits were treated with either a chain of to-bramycin antibiotic-impregnated cement beads, beads without antibi-otics, systemic antibiotics only, or nothing.25 At 5 days, no recoverable organisms were found in six of eight animals treated with antibiotic-impregnated cement beads Six of eight rabbits receiving systemic tobramycin had wound infections All five animals in which nonantibi-otic-impregnated cement beads were implanted had significant infections; one died from sepsis All four ani-mals that received no treatment were infected

Antibiotic concentrations were measured in wound drainage fluid, urine, and serum from 50 patients who underwent primary total hip arthroplasty (THA) and received tobramycin or vancomycin deliv-ered either in antibiotic-impregnated cement or by intravenous adminis-tration (not both).26 No significant differences were found between

Table 2

Antibiotics Used in Antibiotic-Impregnated Cement

Decreased Activity Because Adversely Affected Can Be Mixed With Cement of Cement Heat by Cement Curing

Amikacin Cefuzonam Erythromycin Penicillin Chloramphenicol Liquid gentamicin,

Amoxicillin Cephalothin Gentamicin Polymyxin B Colistimethate clindamycin, etc (because Ampicillin Ciprofloxacin (powder) Streptomycin Tetracycline of aqueous content)

Bacitracin Clindamycin Lincomycin Ticarcillin Rifampin

Cefamandole (powder) Methicillin Tobramycin

Cefazolin Colistin Novobiocin Vancomycin

Cefuroxime Daptomycin Oxacillin

Simplex and Palacos

surgeon-prepared antibiotic-impregnated

cement Serum and urine antibiotic

levels were significantly (P ≤ 0.05)

higher in the intravenous group

than in the impregnated-cement

group Wound drainage fluid levels

of tobramycin were significantly (P

≤ 0.05) higher in the

antibiotic-impregnated cement group than in

the intravenous group, whereas the

vancomycin intravenous group had

higher antibiotic levels in wound

drainage fluid than did the

van-comycin cement group In the

cement group, tobramycin exhibited

a consistently high level of bioactivity

against S epidermidis in wound

drainage fluid, while vancomycin

lost all bioactivity by 24 hours In

30% of cases, no vancomycin was

detected in the wound drainage

fluid of the cement group Overall,

tobramycin exhibited adequate local

tissue levels and released antibiotic

effectively, whereas vancomycin

exhibited inadequate elution

prop-erties

Clinical Studies

Primary Total Joint

Arthroplasty

Because of the low rates of

infec-tion experienced with total joint

arthroplasty procedures, researchers

seeking to demonstrate statistically

significant differences with the

pro-phylactic use of

antibiotic-impreg-nated cement require a very large

sample size with multicenter

partici-pation A prospective, randomized

study in Sweden combined results

from nine orthopaedics departments

(1,688 consecutive THAs) to

com-pare the prophylactic effect of

systemic antibiotics to that of

genta-micin-impregnated cement alone

At a mean follow-up of 10 years, the

infection rate was 1.6% in the

sys-temic antibiotic group and 1.1% in

the gentamicin-impregnated cement

group, a difference that was not

sta-tistically significant.11 No cases of nephrotoxicity, ototoxicity, or aller-gic reaction were reported

More than 10,000 primary ce-mented total hip replacements done for osteoarthritis and reported to the Norwegian arthroplasty registry were studied retrospectively.27 Four groups were compared: patients receiving antibiotic prophylaxis both systemically and locally in antibiotic-impregnated cement, those receiv-ing antibiotics only systemically, those receiving only antibiotic-impregnated cement, and those receiving no antibiotic prophylaxis

The antibiotic-impregnated cement was either Palacos with gentamicin

or AKZ (erythromycin and colistin with Simplex) The rate of revision done for any reason was 2.0%

(94/4,586) in patients receiving only systemic antibiotics, 4.2% (10/239) for antibiotic-impregnated cement only, 1.2% (70/5,804) for the com-bined regimen, and 2.5% (7/276) for

no antibiotics Among cases that sub-sequently required revision for in-fection, the lowest revision rate, 0.14% (8/5,804), was in patients who received both antibiotic-impregnated cement and systemic antibiotics

A prospective, randomized clini-cal trial of 401 patients in two British centers compared the effect

of cefuroxime-impregnated cement and cefuroxime administered sys-temically on infection after total joint arthroplasty.28 No statistically significant difference was found between the two groups with respect to incidence of superficial wound infection or early deep infec-tion (1% in both groups) There were no late deep infections after 2-year follow-up

Hope et al29 found at least one strain of gentamicin-resistant coag-ulase-negative staphylococcus in 30

of 34 cases of deep infection (88%) in which cement containing gentamicin had been used In contrast, only 9

of 57 patients (16%) in whom antibi-otic-free cement was used exhibited

gentamicin-resistant coagulase-neg-ative staphylococcus

Revision Arthroplasty

Revision arthroplasty usually is accompanied by rates of infection significantly higher than rates for primary arthroplasty Revision arthroplasties done for infection are either one- or two-stage procedures Two-stage revisions are more com-mon, but they can be technically demanding because of scar forma-tion, limb shortening, disuse osteo-porosis, and altered anatomy Although advocates of two-stage reimplantation cite infection rates lower than those of one-stage revi-sions, carefully selected patients can

be treated with comparable success with one-stage revisions using antibiotic-impregnated cement In one review of the literature, success rates of one-stage exchange with and without the use of antibiotic-impreg-nated cement were 81% and 71%, respectively; the success rates of two-stage reimplantation with and without antibiotic-impregnated cement were 93% and 82%.30

One-Stage Revision for Infection

One-stage exchange arthroplasty using antibiotic-impregnated ce-ment has been advocated in defined instances for the treatment of an infected total joint arthroplasty In a multicenter comparison of one- and two-stage exchange arthroplasties for infection conducted in the 1970s,

a success rate of approximately 80% was found for both methods.31

Gentamicin-loaded Palacos and 6 months of systemic antibiotics were used in all procedures The results were slightly better for one-stage exchanges; however, follow-up was relatively short (0.5 to 3.5 years) In

a study of 235 one-stage exchanges for THA infection using antibiotic-impregnated cement, 11% with per-sistent infection failed; another 3% of cases with suspected infection failed.32 Of the 61 two-stage ex-changes, which used

antibiotic-impregnated cement beads for

peri-ods of from 6 weeks to 9 months, 5%

failed from reinfection Hope et al29

reviewed a series of 91 patients with

deep infection of a cemented

THA caused by coagulase-negative

staphylococcus In this series, 72

pa-tients were treated with one-stage

exchange arthroplasty; 9 (13%)

failed because of recurrence of

infec-tion Gentamicin was used in

com-bination with other antibiotics based

on organism sensitivities The other

19 patients underwent a two-stage

exchange without any failures

Although it has been suggested

that a contraindication to one-stage

reimplantation is infection with a

gram-negative organism, a study of

15 patients with gram-negative

infection treated with one-stage

THA revision found only 1

recur-rence (6.7%) at a mean follow-up of

8 years Palacos cement with

gen-tamicin was used in 13 of 15

pa-tients, with other antibiotics added

to cement as appropriate.33 In a

larger study of 183 patients with

similar follow-up (mean, 7.75 years),

one-stage revision with both

antibi-otic-impregnated cement and

sys-temic antibiotics was used for deep

infection of a THA.34 Twenty-nine

of these patients (16%) had evidence

of persistent infection and 154 (84%)

were free of infection on follow-up

None of the 29 patients who

experi-enced failure was infected with

gram-negative organisms

For patients undergoing revision

arthroplasty, Garvin et al35

devel-oped a classification system of

high-risk, suspicious, and definite

infection categories These were

based on Gram stains, cultures,

intraoperative findings, clinical

diag-noses, radiographic findings, and

laboratory results.35 In a

prospec-tive clinical study,

gentamicin-impregnated Palacos was used for

prosthesis fixation in 67 high-risk,

32 suspicious, and 31 definite

infec-tions All but one of the high-risk

patients underwent one-stage

pro-cedures; those with suspicious or definite infections underwent either one- or two-stage procedures plus 6 weeks of intravenous antibiotics

Postoperative infection occurred in

5 of the 92 one-stage patients (5.4%) and in none of the 38 two-stage patients Of the 67 high-risk patients, 3 (4.5%) developed post-operative infections; one was then revised with a successful two-stage procedure Of the 32 patients suspi-cious for infection, 19 underwent one-stage implantation; one of them developed a postoperative infection

The other 13 patients with suspi-cious infection underwent success-ful two-stage implantation Of patients with definite infection, 7 of

31 underwent one-stage implanta-tion, with one of them developing a postoperative infection; 24 patients had a successful two-stage implan-tation

To test that one-stage revisions can be successful if rigid criteria are met, Ure et al36 prospectively fol-lowed 20 consecutive patients under-going one-stage THA for infection between 1979 and 1990 Surgical management included meticulous débridement, use of antibiotic-impregnated cement, and systemic antibiotic therapy Patients were excluded from this treatment when they were immunocompromised, had an infection with a known resis-tant gram-negative or methicillin-resistant organism, or had a major skin, soft-tissue, or osseous defect

At a mean follow-up of 9.9 years, no patient had experienced recurrence

of infection Two patients required revision for aseptic loosening

Parenteral antibiotics were adminis-tered postoperatively for a mean of 4.7 months

Two-Stage Revision for Infection

By reducing dead space, cement spacers help stabilize the limb awaiting reimplantation (Fig 1)

Complications include bone loss, dislocation, continued pain, de-creased mobility, and (rarely)

frac-ture Local antibiotic delivery with cement spacers, cement beads, or a PROSTALAC has been used after component removal in a two-stage procedure Additionally, antibiotic-impregnated cement can be used for prosthesis fixation during reimplan-tation in the second stage

Antibiotic-impregnated cement spacers used in the first stage of two-stage reimplantation can

deliv-er a high concentration of antibiotics

to the infected area In a retrospec-tive study, Calton et al37treated 25 infected total knee prostheses in 24 patients with débridement, compo-nent removal, and insertion of an antibiotic-impregnated cement block Intravenous antibiotics were admin-istered for 6 weeks; patients’ knees were kept immobilized with no weight bearing The success rate was 92% (2 failures) at a mean fol-low-up of 36 months; 15 of 25 knees exhibited either tibial or femoral bone loss caused by invagination of the cement spacer block into the cancellous bone Leunig et al38 re-ported on 12 patients with deep infections of hip implants who un-derwent two-stage revision and were treated using gentamicin-loaded cement Spacers were used for a mean of 4 months; during that period, six spacers failed, five by dislocation and one by fracture At

a mean follow-up of 27 months after reimplantation arthroplasty, all patients were mobile and infection free

An articulating spacer used in two-stage revision for infected total knee arthroplasty may improve patient mobility and allow partial weight bearing This would pro-mote healthier soft tissues, improve wound healing, allow easier reim-plantation, improve bone quality and range of motion, and reduce complications Hofmann et al39

treated 26 patients who had late-infected total knee arthroplasties with two-stage revision using an articulating spacer with

tobramycin-impregnated cement The spacer

was prepared by cleaning,

autoclav-ing, and reinserting the femoral

component A new tibial

polyethyl-ene insert and in some cases a new

all-polyethylene patellar component

were used to place a large amount

of antibiotic-impregnated cement

between each insert and bone

Patients were treated with 6 weeks

of intravenous antibiotic therapy

Reimplantation was performed 6 to

12 weeks after placement of the

spacer All but one patient (who

died of systemic complications)

underwent successful

reimplanta-tion (96%) At a mean follow-up

of 31 months, knee scores had

improved and no recurrence of

in-fection was found

Complications of early

articulat-ing spacers included tibiofemoral

instability and patellar instability;

results subsequently have improved

with design modifications A recent

study by Fehring et al40 failed to

show any difference in range of motion or knee scores between articulating and static antibiotic-impregnated cement spacers used

in two-stage revisions The ar-ticulating spacers were custom-pre-pared using a stainless steel femoral component mold and stemmed tibial baseplate of antibiotic-impregnated cement Nevertheless, reimplanta-tion was facilitated, and less bone loss occurred with articulating spac-ers than with static antibiotic-impregnated spacers

Lai et al41 reported on 40

infect-ed hip prostheses treatinfect-ed with component removal, intravenous and oral antibiotics for 8 weeks, and delayed reimplantation (mean,

48 weeks) with cementless compo-nents At mean of 4 years’

follow-up, 5 patients (13%) had experi-enced recurrent infection: 2 of 33 from the group treated with Sep-topal (gentamicin) beads, and 3 of 6

of those treated without

antibiotic-impregnated cement beads A pro-spective, randomized, multicenter study of 6 infected total knee and 22 infected hip arthroplasties in 28 patients compared two-stage re-implantation using gentamicin-impregnated cement beads with that using conventional parenteral systemic antibiotic therapy for 6 weeks postoperatively.42 At a mean follow-up of 3 years, infection recurred in 2 of 15 patients treated with gentamicin-impregnated cement beads (13%) and in 4 of 13 patients treated with conventional systemic antibiotic therapy (31%); however, this was not statistically significant Whiteside43used allo-graft technique with cementless revision arthroplasty for massive tibial and femoral defects in 33 chronically infected total knee arthroplasties Treatment included implant removal, débridement, and rigidly fixed antibiotic-soaked bone graft followed by 6 weeks of antibi-otic-impregnated cement beads and intravenous antibiotics The success rate of the two-stage procedure was 85% Infection recurred in five knees; however, repeated procedures al-lowed successful revision in all but one, which required an above-the-knee amputation Although use of antibiotic-impregnated cement beads

or spacers is common in two-stage revisions, one study showed that their use in two-stage revisions was not correlated with cure rate for infection.44

The PROSTALAC, introduced in

1989, is a temporary hip prosthesis composed of a thin polyethylene acetabular cup and a stainless steel femoral component, both of which are loosely cemented with antibiotic-impregnated cement (Fig 2) Bene-fits include early mobilization, accel-erated rehabilitation, and early hos-pital discharge The device maintains soft-tissue planes and leg lengths and has made second-stage proce-dures easier to perform Younger et

al45reviewed 48 patients who had

Figure 1 Anteroposterior (A) and lateral (B) radiographs of an antibiotic-impregnated

cement spacer in a two-stage revision total knee arthroplasty.

undergone two-stage arthroplasty of

an infected hip replacement using

the PROSTALAC All but three

pa-tients were free from persistent

infection, for an eradication rate of

94% More recently, Younger et al46

evaluated PROSTALACs with a

cement-on-cement articulation and

with a custom

metal-on-polyethyl-ene articulation Of 28 infected total

hips followed for a minimum of 2

years, 96% exhibited no evidence of

infection

In a retrospective study of 89

re-vision procedures for infected total

knee arthroplasties, persistent

infec-tion occurred in 10 knees (11.2%).44

No standardized protocol was used

for treatment In 64 knees,

antibiotic-impregnated cement was used for

implant fixation; in 25, no

antibiotic-impregnated cement was used

Antibiotic-impregnated beads were

used in 20 patients,

antibiotic-impregnated spacers in 23, both

used in 4, and neither used in 42

patients When use of

antibiotic-impregnated cement for implant

fix-ation was factored in, the results

were statistically significant Of the

25 knees without antibiotic-impreg-nated cement, 7 (28%) developed recurrent infection, compared with only 3 (5%) of the 64 knees treated with antibiotic-impregnated cement

(P < 0.01) Although

antibiotic-impregnated cement beads or spac-ers appeared to be beneficial, their use was not statistically significant

We are not aware of any prospec-tive randomized study comparing antibiotic-impregnated cement beads or spacers to antibiotic-impregnated cement in prosthetic fixation

Antibiotics in Revision Arthroplasty Without Infection

Although the use of antibiotic-impregnated cement in revision arthroplasty without evidence of infection has been advocated, the literature on the subject is scant and equivocal Lynch et al47 reported notably better results with genta-micin-containing cement for aseptic revisions than with cement alone (systemic antibiotics not used), a reduction from 3.5% to 0.8% A ret-rospective analysis with minimum 2-year follow-up reported that in aseptic revision THAs or conversion from upper femoral prosthesis (pro-phylactic systemic antibiotics not used), infection rates were 0.5% for gentamicin-impregnated cement and 2.8% for cement alone.47 The authors concluded that low-viru-lence organisms that are difficult to culture may be present in some cases thought to be aseptic loosen-ing and that the local antibacterial effect is responsible for the effective prevention and treatment of infec-tion in these patients

Experimental Cement-Antibiotic Combinations

Ceramic composites have been considered for use as a vehicle for antibiotic delivery In one laboratory study of a novel bioactive bone ce-ment (15% bisphenol-α-glycidyl methacrylate, 15% triethylene-glycol

dimethacrylate resin, and 70% apatite- and wollastonite-containing glass-ceramic powder) containing cephalexin in the form of pellets, antibiotic release was initially rapid, slowed markedly after 24 hours, and was released continuously thereafter for 2 weeks.48 The strength of the cement with cephalexin was approxi-mately twice that of acrylic antibiotic-impregnated cement The authors suggested that this material may be suitable for prosthetic fixation as well as in beads or spacers Another study tested the efficacy of a calcium hydroxyapatite ceramic with gen-tamicin in the form of blocks im-planted adjacent to stainless steel tibial inserts in rats that had been

in-jected with S aureus.49 Suppression

of infection in the ceramic-genta-micin–treated animals was superior

to that in controls, including those in which acrylic

antibiotic-impregnat-ed cement was usantibiotic-impregnat-ed

Biodegradable antibiotic-impreg-nated material offers a potential means of local antibiotic delivery for infection control or treatment with-out obligation for later removal A biodegradable cement (composed of tricalcium phosphate and calcium carbonate with a matrix phase of polypropylene fumarate cross-linked with methylmethacrylate monomer) containing gentamicin and vancomycin was evaluated for

treatment and prophylaxis of S

aureus osteomyelitis in rat proximal

tibias.50 The treatment group

exhib-ited significantly (P < 0.01) fewer

colony-forming units than did con-trols Sites treated prophylactically developed no infections No signifi-cant difference was found between biodegradable cement and PMMA used as a carrier for antibiotics Another study showed that the ten-sile strength of the material and the biologic activity of the antibiotic were maintained when gentamicin was added to a resorbable calcium phosphate cement composed of

β-tricalcium phosphate,

monocal-Figure 2 Anteroposterior radiograph of

the PROSTALAC in a two-stage revision

THA.

cium phosphate monohydrate, and

water.51

More recently, calcium

hydrox-ide has been added to PMMA beads

containing tobramycin.52 The beads

released hydroxyl and calcium ions

into the culture medium as well as a

greater amount of antibiotic than

did beads containing only

tobramy-cin Bacterial growth was more

effectively inhibited when S aureus

was incubated with

tobramycin-and calcium

hydroxide–impregnat-ed PMMA disks than with disks

containing only tobramycin The

study did not, however, address the

effects of the tobramycin and

calci-um hydroxide combination on the

strength of the cement Future uses

may include fracture healing and

bone grafting in addition to

osteo-myelitis treatment and implant

attachment

Summary

Since its introduction in 1970, antibi-otic-impregnated cement has been used in total joint arthroplasty in a variety of situations In both one-and two-stage revision procedures for infection, antibiotic-impregnated cement clearly reduces the reinfec-tion rate The antibiotic should

be chosen based on the infecting organism or, if preoperative cul-tures are unavailable, by assessment

of likely pathogens In two-stage procedures, the use of articulating spacers implanted with antibiotic-impregnated cement may improve reimplantation results as well as quality of life in the period between procedures There is some sugges-tive evidence that if cement is to be used in apparently aseptic revision surgery cases, the cement should be

antibiotic-impregnated because of the possibility that these culture-negative cases are indeed contami-nated Because of the low rate of infections with established periop-erative and intraopperiop-erative protocols and the risk that using antibiotics will lead to the development of antibiotic-resistant bacteria, the rou-tine use of antibiotic-impregnated cement appears to be unnecessary

in primary total joint replacement surgery The future of antibiotic-impregnated cements may include stronger composites with more sus-tained release of a wide array of an-tibiotics Bioabsorbable antibiotic-impregnated cements may further reduce reinfection rates in one-stage procedures by supplying additional local delivery of antibiotic via mate-rials that do not require later re-moval

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