Download Review Antimicrobial prophylaxis in orthopaedic surgery: the role of

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Journal of Antimicrobial Chemotherapy (1998) 41, 329–340
Review
Antimicrobial prophylaxis in orthopaedic surgery: the role
of teicoplanin
Piero Periti*, Enrico Mini and Giorgio Mosconi
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy
Orthopaedic joint replacement is generally considered ‘clean’ surgery characterized by a low
incidence of infection. In recent years the use of a clean theatre environment, high local
concentrations of antibiotic in the cement and systemic antibiotic prophylaxis have been
recognized as important measures to reduce infection rates significantly, and this has been
supported by clinical trials. Staphylococcus aureus and Staphylococcus epidermidis cause at
least half of all orthopaedic surgical infections. Gram-negative bacilli are involved to a much
lesser extent (10–30%). First- and second-generation cephalosporins are currently considered
by most authors as standard prophylaxis in elective orthopaedic surgery. In the light of the
increasing incidence of methicillin resistance in coagulase-positive and -negative staphylococci, it is becoming more important for antibiotics to act efficiently against such organisms if
they are to be of value in prophylaxis in orthopaedic surgery. A combined, single-dose of
vancomycin/gentamicin has been used successfully in an open, controlled study in patients
undergoing total joint arthroplasty but, given the disadvantages associated with the use of
vancomycin, teicoplanin may be an alternative choice in such procedures. This review
analyses four comparative trials of the efficacy and safety of teicoplanin, two with
cefamandole, one with cefuroxime and one with cephazolin, as prophylaxis in orthopaedic
total joint replacement surgery.
Introduction
The replacement of diseased or damaged joints with
prostheses is a major accomplishment of modern orthopaedic surgery. Currently, infection represents the most
feared and, perhaps, the most serious complication of
prosthetic joint surgery.1 Although it occurs in only a small
proportion of patients, the large number of such procedures performed annually makes this problem significant, and when infection does occur the outcome can
be devastating, resulting in total loss of joint function,
amputation and, occasionally, death.2 Consequently, antimicrobial prophylaxis, usually reserved for contaminated
orthopaedic surgery, is today also recommended for any
clean procedure involving implantation of orthopaedic
prostheses to prevent the severe clinical and economic
consequences of sepsis.3,4
Infection in an orthopaedic prosthesis has been
arbitrarily classified as ‘early’ if it occurs within 3 months
of placement. Infection occurring within this time-frame is
generally considered to be caused by the ingress of
bacteria during the peri-operative period. Infection after
3 months is classified as ‘late’, and usually occurs within
the first year.5 Such infections tend to be low grade, to
develop slowly and to be difficult to diagnose, and can be
the consequence of blood-borne infection, though the
cause may also be from the few organisms seeded at the
time of operation.6–12
In most orthopaedic surgical procedures the bacterial
contamination and eventual infection are usually from an
exogenous source; the organisms most commonly causing
deep wound infection are Staphylococcus aureus and
coagulase-negative staphylococci (particularly Staphylo coccus epidermidis). Other organisms isolated from
infected prosthetic joints include aerobic and anaerobic
streptococci and a variety of Gram-negative
*Corresponding address: Viale G. B. Morgagni 65, 50134 Firenze, Italy. Tel: +39-55-431720; Fax: +39-55-4361613.
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© 1998 The British Society for Antimicrobial Chemotherapy
P. Periti et al.
bacilli.1,2,11,13–16 Factors increasing the incidence of infection include the duration of the operation, the length
of preoperative hospitalization, rheumatoid arthritis,
previous surgery performed on the joint, and the anatomic
site. The rate of infection in clean orthopaedic surgery
varies according to the procedure performed. Reported
rates of deep infection are 1.3–11% in total hip replacement, and 0.7–9% in knee arthroplasty.17 The infection
risk in elective orthopaedic surgery involving prosthetic
implants is, on average, significantly greater in total knee
replacement than in total hip replacement.11
Avoiding prosthetic contamination upon insertion is
mandatory, and the use of laminar flow has been shown to
be an important preventive measure.18 There is now
conclusive evidence that hypersterile operating conditions
decrease the number of air-borne organisms, and can significantly reduce the infection rate compared with surgery
performed in conventional operating theatres.7,18–20
Additional factors that have led to a decrease in the
frequency of infection following total joint arthroplasty in
recent years include improved surgical technique and the
use of ultraviolet light, antibiotic-impregnated methylmethacrylate and systemic prophylactic antibiotics.21–25 Of
the measures most commonly used to reduce the risk of
infection in orthopaedic implants (i.e. ultraclean air in
vertical unidirectional flow, and antibiotics used systemically or in cement), and those taken to avoid infection
common to all surgery, the most powerful procedure is the
use of antibiotics.26 These authors found that systemic
prophylaxis reduced the infection rate of 3.4% that is
found in conventionally ventilated theatres by four-fold,
and that ultraclean air systems reduced it by another half.
Protective clothing, such as body-exhaust suits, helped
further reduce infection by 0.5%.
Principles of antimicrobial prophylaxis in
orthopaedic surgery
Today, arguments centre around the timing of dosage,
duration, route of administration and choice of prophylactic antibiotics rather than the need for their use; failure
to use antibiotics has been estimated to result in a sevenfold increase in the rate of infection.7 Many studies have
now established that timing is critical to the efficacy of
surgical antimicrobial chemoprophylaxis; antibiotic
treatment must be given before surgery in order to ensure
high levels in the tissues at the time of contamination.16,27,28 However, to achieve optimum effects, the
antibiotic should not be administered too early in the preoperative period.3,7,17
As in other branches of surgery, providing the kinetics
and timing are correct, there is emerging evidence in
orthopaedic surgery that single-dose prophylaxis is
adequate and that additional peri-operative antibiotics
should not be necessary.16,18,28–33 Optimum antiseptic
efficacy is achieved when an antimicrobial agent is
administered intravenously to provide at equal dose the
highest blood concentrations, and thus the maximum
and most rapid penetration into the extravascular
compartment.34 The interval between intravenous dosing
and the start of surgery should be reduced to 20–30 min to
allow saturation of bone, joint soft tissue or haematoma.18
The half-life of the drug determines the number of perioperative doses needed to ensure maximum antiseptic
efficacy using the minimum amount necessary to provide
full antimicrobial cover. A single, pre-operative dose can
provide optimum chemoprophylaxis when the half-life is
longer than the surgery time.7,16,18,35–38
Tissue penetration of antibiotics active against
Gram-positive bacteria
In orthopaedic surgery the chemoprophylactic agent must
reach the bone and surrounding soft tissues at adequate
concentrations during the operation (i.e. at the time of
potential bacterial contamination). Although data from
clinical studies are scarce, adequate concentrations at the
time of surgery should be well in excess of the mean
MIC for the bacteria most often causing postoperative
infections of the wound, if the outcome is potentially lifethreatening.18,32,37,39
Antibiotics that have been reported to penetrate bone
well are clindamycin, gentamicin, flucloxacillin, cephazolin, cefamandole, cefuroxime, cefoxitin, ceftriaxone,
ceftazidime, rifampicin, ofloxacin, pefloxacin, vancomycin
and teicoplanin.35,40–57
Teicoplanin is widely distributed in a variety of tissues
and fluids, except for cerebrospinal fluid. Concentrations
in bone are 65% of those in serum, and the peak is reached
within 0.5–6 h after rapid, intravenous administration of
teicoplanin 400 mg. The results at the end of surgery
suggest that levels in excess of the MIC90 of Gram-positive
cocci, S. aureus and S. epidermidis as well as enterococci,
will be obtained in serum and bone for 3 h.58 On the
basis of the favourable pharmacokinetic characteristics
described, as well as the antimicrobial properties (i.e.
activity against Gram-positive bacteria) and the low
toxicity, the first- and second-generation cephalosporins
(such as cephazolin, cefamandole and cefuroxime) are
considered the prophylactic antibiotics of choice in total
hip or knee replacement.7,13,20,28,59–62 In particular, cephazolin has been the most often used and recommended
agent in this setting.20,59–63 After an intravenous bolus
dose of cephazolin 2 g, bone concentrations are well above
the MBC for methicillin-susceptible staphylococci.62
However, there is a real need for alternative antibiotics,
such as the fluoroquinolones and glycopeptides
(vancomycin and teicoplanin). The pharmacokinetic data
and activity of these agents against Gram-positive
bacteria, including -lactamase-producing and methicillin-
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resistant staphylococci, qualify them as effective agents to
provide valid peri-operative prophylactic cover.46,64–70
Choice of antibiotic
As most infections in joint prostheses are caused by
staphylococci, antibiotic prophylaxis is generally directed
against Gram-positive bacteria. Cephalosporins, semisynthetic penicillins, fluoroquinolones and glycopeptides
have the desired spectrum of activity, safety and tissue
penetration.13,35,39,62,64,65,67,71 The most widely used antibiotics in total joint replacement procedures are the firstand second-generation cephalosporins by virtue of their
excellent activity against the pathogens commonly
involved in joint prosthesis infections, and their favourable
pharmacokinetics and safety.13,62,63,71 The preferred agents
are cephazolin and cefamandole. Multiple doses (pre- and
post-intervention) of cephazolin are today considered by
most authors as standard prophylaxis during clean surgical
procedures, including elective orthopaedic surgery, if
methicillin-resistant staphylococci have not been isolated
in the nosocomial environment.10,20,22,31,59,61,72–77
Pefloxacin has been the only fluoroquinolone to be
studied as a prophylactic agent in hip or knee replacement
surgery.78–82 It has been shown to be as effective and welltolerated as comparative cephalosporins (cefamandole,
cephazolin, ceftazidime and ceftriaxone).79–82 The
inhibitory activity of these drugs is, however, somewhat
lower against staphylococci than Gram-negative bacteria,
and staphylococcal MICs are generally close to the breakpoint of susceptibility. There is also evidence of increasing
staphylococcal resistance, particularly in methicillinresistant strains, during treatment with fluoroquinolones.
This has been associated with the extensive use of these
antibiotics in the hospital setting.83–86
The glycopeptide antibiotics, teicoplanin and vancomycin, represent valid alternative for prevention of
infection following orthopaedic surgery.13,64,71 Considering
the growing incidence of methicillin-resistant coagulasepositive and -negative staphylococci in nosocomial
infections, it is becoming more important for antibiotics to
act efficiently against these bacteria if they are to be of
value for prophylaxis in orthopaedic surgery.84,87,88 A
combined, single-dose vancomycin/gentamicin regimen
has been used successfully in an open, controlled study in
patients undergoing unilateral or bilateral total joint
arthroplasty.89 Recommendations for the use of vancomycin alone as an alternative peri-operative antimicrobial
prophylactic agent in orthopaedic prosthetic surgical
procedures have been made.31,32,71,90–92 However, vancomycin is more difficult to administer (by long-term
intravenous infusion only) and has a shorter half-life than
teicoplanin. Results of a recent meta-analysis of 11
randomized, clinical trials conducted in patients with
either febrile neutropenia or severe Gram-positive
infections, including those with methicillin-resistant S.
aureus, suggest that vancomycin is as effective as teicoplanin, but is tolerated significantly less well.93 Perioperative antibiotic prophylaxis with vancomycin is also
characterized by anaphylactoid reactions, such as
significant hypotension and the ‘red man’ syndrome.92,94,95
Teicoplanin may be an optimal choice in this setting as it is
active against staphylococci, including methicillin-resistant
strains.64,96,97 Teicoplanin has a long half-life, low toxicity
and good tissue penetration, 64,98 which allows it to achieve
therapeutically valid concentrations in bone and the
surrounding soft tissue (references 51,57,65, and Garaud,
J. J., Cavenaghi, L. & Girat, T., data on file, Merrell Dow
Research Institute). The recent recognition of increasing
resistance to glycopeptides among Gram-positive bacteria,
however,99–101 has caused concern that glycopeptideresistant strains of S. aureus and coagulase-negative
staphylococci will assume clinical importance.102 This
makes it prudent to limit the use of these agents for shortterm antimicrobial prophylaxis in orthopaedic surgical
procedures in institutions in which methicillin-resistant
S. aureus or S. epidermidis are important wound
pathogens,103 or in patients allergic to -lactam antibiotics.
Clinical trials with teicoplanin
Studies
Four comparative trials of the efficacy and safety of
teicoplanin as antimicrobial prophylaxis in orthopaedic
surgery have been performed. Two were carried out in the
UK, and compared teicoplanin with cefuroxime,104 or
cefamandole,72 while the other two were conducted in
Italy and compared teicoplanin with cefamandole or
cephazolin.73–74,77
The first pivotal trial was an unblinded, randomized
study comparing a single dose of teicoplanin against four
cefamandole doses over a 24 h period in patients undergoing prosthetic joint surgery (hip or knee arthroplasty)
at the Musgrave Park Hospital, Belfast.72 A total of 899
patients was entered into the study; of these 19 did not
receive study medication and were not considered further.
Patients were assessed for evaluability on an ‘intent-totreat’ (n 880) or ‘per protocol’ (n 765) basis (Table I).
Of the 115 protocol violations, most resulted from
inappropriate randomization. Patients were randomly
allocated to two groups to receive either teicoplanin 400 mg
iv at the induction of anaesthesia, or cefamandole 2 g iv at
induction and 1 g every 6 h for 18 h after the operation.
Most patients received gentamicin bone cement during
their operations. The remainder received a cementless
artificial joint. A primary failure was defined as a wound
infection with proven bacteriology. Infections at all other
sites were reported as secondary failures or complications.
Efficacy was determined on the basis of post-operative
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P. Periti et al.
wound infection assessed at 8–10 days, 1 month and 6–18
months post-operation.
The second pivotal clinical study was a multicentre,
comparative, randomized study of a single dose of
teicoplanin compared with five doses of cephazolin in
patients undergoing hip or knee replacement in 12 centres
in Italy. 69,73–74 Patients were randomized to receive either
teicoplanin 400 mg iv at the induction of anaesthesia, or
five doses of cephazolin 2 g at induction plus four 1 g iv
doses spread over 24 h post-operatively. A total of 860
patients was enrolled, and 14 were excluded from data
analysis due to pre-operative protocol violations (i.e.
positive pre-operative urine culture or antibiotic therapy
in the week before surgery). Twenty patients were not
evaluable for efficacy as an unjustified antibiotic treatment
had been administered post-operatively. Thus, 846 and
826 patients were evaluated for safety and efficacy,
respectively (Table I). A primary failure was defined as a
wound infection with or without proven bacteriology.
Infections at other sites were reported as secondary
failures or complications. Early assessments were
performed in the post-operative stay and at 3 months,
while a long-term follow-up was performed at 12 months.
Two further clinical studies were conducted in the UK
and Italy, and compared teicoplanin 400 mg iv at the
induction of anaesthesia with three doses of cefuroxime
and two doses of cefamandole, respectively.77,104
Cefuroxime was administered as three 750 mg iv doses,
one at pre-medication, one at induction of anaesthesia and
one 8 h post-operatively. Cefamandole 2 g iv was given
before surgery and 1 g was given after surgery. In all, 146
patients were enrolled in the UK study (72 receiving
teicoplanin and 74 receiving cefuroxime). The Italian trial
recruited 520 patients, of whom 250 receiving teicoplanin
and 246 receiving cefamandole were evaluable for efficacy
(Table I). In both studies, efficacy was assessed by wound
scores and wound infections during the post-operative
hospital stay.
Exclusion criteria common to all four studies were age
(14 or 18 years), known allergy to study drugs, active
infection or significant bacteriuria at time of operation,
antibiotic therapy in the 2 weeks preceding operation,
pregnancy or lactation, and renal impairment.
The study methods used in the four trials considered
here (including the selected patient populations and
prophylactic regimens) did not differ substantially. The
overall analysis of treatment effects was thus valid. The
statistical methods appropriate for analysing data from
retrospective randomized studies have been described in
detail elsewhere.105,106 All analyses were based on
individual data. Treatment effects on failure and adverse
event rates were estimated initially within each trial, and
then overall. These data were analysed using the
Mantel–Haenszel 2 statistic.105 The results were examined
in terms of odds ratios and their 95% confidence intervals
(CIs). For a first approximation, an odds ratio can be
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thought of as the relative risk of an event occurring in the
teicoplanin group compared with the risk of its occurrence
in the cephalosporin group. An odds ratio between 0 and 1
indicates a benefit of treatment with teicoplanin compared
with cephalosporins, while an odds ratio of 1 indicates a
benefit of cephalosporins over teicoplanin. The benefit is
statistically significant when the 95% CI of the odds ratio
does not include unity. Heterogeneity between trials was
evaluated by the 2 test. Calculations were performed
using appropriate statistical software (Statistica, Release
5.0, 1997 from Stata Corporation, College Station, TX,
USA). Odds ratios and statistical results are reported in
detail for primary failure data (Table II). For all other
efficacy and safety data comparisons, only statistically
significant differences or trends are indicated.
Patient population
The four studies were comparable with regard to major
patient characteristics and risk factors. No clinically
relevant differences were seen among the studies or
between treatment groups for sex distribution, age, body
weight or duration of surgery.
Efficacy
Wound infection. Table II summarizes the efficacy results,
expressed as wound infections, for the four studies of
orthopaedic prophylaxis. Early wound infection rates (i.e.
those occurring within 3 months of the operation) were
comparable for all the studies. In the study by Wall et
al.,104 bacteriology was reported for all patients with
suspected wound infection. However, the number of
wound infections was not evaluated.
In the study by Mollan et al.,72 in the ‘intent-to-treat’
analysis, nine early wound infections (1%) occurred, three
(0.8%) in the teicoplanin group and six (1.2%) in the
cefamandole group. The difference between study
treatments was not significant. Similar results were
obtained analysing data ‘per protocol’. Details are given in
Table II. In the study by Periti et al.,69,73–74 19 early wound
infections were recorded (2.3%), with no difference
between the two treatment groups; nine (2.2%) in the
teicoplanin group and ten (2.4%) in the cephazolin
group.
In the Suter et al.77 study the only infectious complications were seen in the cefamandole group (Table II).
According to these authors, the difference between the
groups was not statistically significant (P 0.059 by using
Fisher’s exact test). Analysis of these data by the Mantel–
Haenszel procedure, however, generated a P value of
0.043, suggesting a significant difference at this significance
level.
The overall wound infection rate seen in the study by
Wall et al. (6.8%) was significantly higher than those
obtained in the other three studies (0.8% in the Suter
study, 1.0% in the Mollan study and 2.3% in the Periti
study).69,72–74,77,104 There was no significant difference
between the regimens in the development of wound
infection (5.5% for teicoplanin and 8.1% for the
comparator cephalosporin cited, i.e. cefuroxime).
Data on long-term assessment at 6–18 or 24 months are
available for the pivotal studies. In the Mollan study, of
the 880 patients enrolled, 6–18-month follow-up reports
are available for 842 patients (95.7%, ‘intent-to-treat’
analysis).72 Three late wound infections occurred; one
(0.3%) in the teicoplanin group and two (0.4%) in the
cefamandole group. In the Periti study, clinical data from
683 patients (79.4%) were available at the 12-month
follow-up.69,73–74 One primary failure was seen in each of
the teicoplanin (0.3%) and cephazolin (0.3%) groups. No
late wound (24-month follow-up) infectious complications
were seen in either treatment group in the Suter study (all
496 patients evaluable).77 No long-term assessment data
are available for the study by Wall et al.104
The pathogens most commonly encountered were
Gram-positive organisms (77.8%, Table III). S. aureus, S.
epidermidis and other coagulase-negative staphylococci
accounted for 53.3% of total isolates. In the study by
Mollan et al.,72 66.7% of pathogens isolated from wound
infections were S. aureus and coagulase-negative
staphylococci. In the Periti study,69,73,74 15 of 21 wound
infections were bacteriologically proven, of which eight
(53.3%) were caused by staphylococci. For the supporting
studies by Suter et al.77 and Wall et al.,104 staphylococci
accounted for 16.7% and 58.3%, respectively, of
pathogens isolated from positive wound cultures.
Table IV gives a breakdown of overall wound infection
rates by the type of joint replacement for the major orthopaedic surgery studies. It has been reported that knee
replacement surgery involves a significantly higher risk
of infection than hip replacement.11 The Mollan study
supports this observation since the overall wound
infection rates on an intent-to-treat basis were 3.2% and
0.8% for knee and hip replacement, respectively.72 The
results of Periti’s study show an inverse trend, even though
the higher wound infection rate seen in hip compared with
knee replacement surgery (1.8% and 0.7%, respectively)
was not significant.69,73–74 No statistically significant
differences were seen between treatment arms in either of
these studies, according to type of joint replacement.
Secondary infections. The incidence of secondary
infections (i.e. infections at sites remote from the wound)
shows agreement between treatment in the three studies in
which this parameter has been evaluated (Table V).72,74,77
Although the overall incidence of wound infection was the
same in the Mollan study, the incidence of urinary tract
infection (UTI) was significantly higher in the teicoplanin
group, with almost twice as many Gram-negative
infections occurring, while the number of lower
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P. Periti et al.
334
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Table III. Wound microbiology in the randomized studies on orthopaedic surgery with
teicoplanin or cephalosporins72,74,77,104
Species
Teicoplanin
Cephalosporin
Total
Gram-positive bacteria
Staphylococcus aureus
coagulase-negative staphylococci
Streptococcus spp.
Enterococcus spp.
other Gram-positive rods
total
4
5
0
0
2
11 (73.3%)
9
6
2
3
4
24 (80%)
13
11
2a
3
6b
35 (77.7%)
Gram-negative bacteria
Escherichia coli and coliforms
Serratia marcescens
Enterobacter cloacae
Pseudomonas aeruginosa
unspecified Gram-negative rods
total
2
1
0
0
1
4 (26.7%)
Unspecified isolates
Negative cultures
Total number of isolates
0
3
15
2
0
1
2
0
5 (16.7%)
1 (3.3%)
4
30
4
1
1
2
1
9 (17.8%)
1 (4.4%)
7
45
a
One Streptococcus sanguis, and one unnamed -haemolytic streptococcus.
Two Clostridium perfringens, one diphtheroid, one Peptococcus sp., one Micrococcus sp. and one unspecified
Gram-positive anaerobe.
b
Table IV. Wound infection rates associated with different types of joint replacement
Knee replacement
Hip replacement
Study
teicoplanin
cephalosporin
teicoplanin
cephalosporin
Mollan et al.72
Periti et al.74
2/92 (2.2%)
1/72 (1.4%)
5/126 (4.0%)
0/74 (0%)
2/294 (0.7%)
5/338 (1.5%)
3/368 (0.8%)
7/342 (2.0%)
respiratory tract infections (LRTIs) was significantly
higher in the cefamandole arm.72 In the Periti and Suter
studies, Gram-negative organisms were the predominant
causative agents of UTI and LRTI in both treatment
groups.74,77 However, it is recognized that antimicrobial
prophylaxis is only beneficial in the prevention of
infections at the surgical site. It has no role in the
prevention of secondary post-operative infections, such as
LRTI and UTI.107
Safety
Tables VI and VII summarize the adverse events seen in
the four studies as total adverse events and adverse events
related to the study drug, as judged by the investigator.
The incidence of adverse events was similar for the two
treatment groups within each study, and was generally
low. In the study by Periti et al.,74 a higher incidence of
adverse events was observed in the cephazolin group
(2.1% vs 0.7% in the teicoplanin group), though this
difference did not reach statistical significance. Also, of
the nine patients with adverse events in the cephazolin
group, only two had events related to the study drug. Of
1140 patients receiving teicoplanin who were evaluable for
safety, the overall incidence of adverse events was 5.1%
(58 patients) of whom 1.0% (11 patients) had events
attributed to the study drug. In comparison, 1252 patients
received cephalosporins, of whom 6.5% (82 patients)
experienced adverse events, with 1.0% (12 patients) being
related to the study drug.
Analyses of laboratory data in the studies by Mollan et
al.72 and Periti et al.74 showed marked changes from
baseline for haematological and biochemical parameters.69,72–74 However, these were comparable between the
treatment groups and considered to be related to the
effects of operation.
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P. Periti et al.
Table V. Summary of incidence of secondary infections for orthopaedic surgery prophylaxis with teicoplanin or
cephalosporins in randomized trials
Study
Drug
Mollan et al.72 teicoplanin
cefamandole
Periti et al.74 teicoplanin
cephazolin
Suter et al.77 teicoplanin
cefamandole
a
P = 0.0027; bP
0.048; cP
Fever
Thrombo- Asymptomatic
phlebitis bacteriuria
UTI
LRTI
Antibiotic Other
therapy
infections
1 (0.3%)
4 (0.8%)
36 (8.8%)
41 (9.8%)
72 (27.7%)
71 (27.3%)
–
–
2 (0.5%)
2 (0.5%)
–
–
0
5 (1.0%)b
4 (1.0%)
1 (0.2%)
7 (2.7%)
7 (2.7%)
21 (5.4%)
39 (7.9%)
7 (1.7%)
3 (0.7%)
–
–
–
–
3 (0.7%)
9 (2.2%)c
–
–
18 (4.7%)
10 (2.0%)a
4 (1.0%)
2 (0.5%)
12 (4.6%)
13 (5.0%)
1 (0.3%)
0
2 (0.5%)
0
1 (3.8%)
1 (3.8%)
0.086.
Table VI. Summary of adverse events in randomized studies for orthopaedic surgery prophylaxis with
teicoplanin or cephalosporins
Patients with adverse
events
Patients with adverse events
related to the study drug
Study
Drug
n
%
n
%
Mollan et al.72
teicoplanin
cefamandole
teicoplanin
cefazolin
teicoplanin
cefamandole
teicoplanin
cefuroxime
teicoplanin
cephalosporins
43
61
13
19
11
12
11
10
58/1140
82/1252
11.1
12.3
10.7
12.1a
10.4
10.8
15.3
13.5
15.1
16.5
14
12
10
12
11
12
16
16
11/1140
12/1252
1
0.4
0
0.5
0.4
0.8
8.3
8.1
1.0
1.0
Periti et al.74
Suter et al.77
Wall et al.104
Total
a
P
0.083
Table VII. Adverse events possibly related to study drugs
Teicoplanin
Cephalosporin
Study
adverse event (n)
total
adverse event (n)
total
Mollan et al.72
allergic reaction (2)
transient hypotension (1)
deep vein thrombosis (1)
0
4 (1%)
allergic reactions (2)
2 (0.4%)
0
itch (1)
diarrhoea (1)
allergic reactions (2)
hypotension (1)
deep vein thrombosis (4)
intestinal obstruction (1)
2 (0.5%)
Periti et al.74
Suter et al.77
Wall et al.104
allergic reactions (1)
nausea (1)
deep vein thrombosis (2)
pyrexia (1)
suspected pulmonary embolism (1)
swollen ankle (1)
1 (0.4%)
6 (8.3%)
336
2 (0.8%)
6 (8.1%)
Review
Conclusions
It can be concluded, on the basis of results of the four
randomized studies, that single-dose teicoplanin has
efficacy and safety equivalent to multiple-dose cephem
antibiotics (cephazolin, cefamandole or cefuroxime) in the
prevention of post-prosthetic joint infection. The number
of patients required to show a statistical difference is large.
For example, to demonstrate a reduction in infection rate
from 2% to 1% with a power of 90% at the 95% CI, a
study would need over 3000 patients per group. The
practicalities of producing a trial in this area with such
large patient numbers makes demonstrating such a
difference unlikely. The studies presented here included
2406 patients, of whom 2233 were evaluable for efficacy on
a ‘per protocol’ and 2348 on an ‘intent-to-treat’ basis. The
two major studies together represent 1740 patients, of
whom 1591 were evaluable. The infection rates seen in the
two pivotal studies were 0.5–1.5% for teicoplanin and
0.4–1.7% for the comparator cephalosporin at the early
assessment within 3 months of operation. At the long-term
assessments, conducted 6–18 months post-operation,
wound infection rates were 0.3% in both studies for
teicoplanin and 0.3–0.4% for the comparator
cephalosporins. These rates are comparable to published
studies of antimicrobial prophylaxis in orthopaedic
surgery, where rates of 0.5–4% have been reported
following prophylaxis with cephalosporins, such as
cephazolin, cefamandole and cephaloridine. Some of these
studies used up to 5 day dosing regimens of the prophylactic antibiotic. No significant difference in the incidence
of adverse drug events between teicoplanin and the
comparator cephalosporins was observed.
The microbiological results of the four studies confirm
that Gram-positive bacteria are the primary pathogens
responsible for wound infection in prosthetic joint surgery,
accounting for approximately 78% of isolates. S. aureus
and coagulase-negative staphylococci were predominant
(about 53%). The results from these studies demonstrate
that a single, peri-operative dose of teicoplanin can
represent a valid alternative to multiple administration of
antimicrobial drugs with a short half-life in preventing
infection following total hip and total knee replacement.
Teicoplanin has a good spectrum of antimicrobial activity
against primary pathogens responsible for wound
infection in orthopaedic surgery. In particular, it is highly
active against staphylococci, both methicillin-sensitive and
methicillin-resistant strains, which are the most common
pathogens in prosthetic orthopaedic surgery. Teicoplanin
also has excellent tissue penetration and low toxicity. Its
elimination half-life is exceptionally long, outlasting the
mean operating times in orthopaedic implant surgery,
making it suitable for peri-operative prophylaxis.
Teicoplanin as a single 400 mg dose by rapid intravenous route at induction of anaesthesia may represent a
reasonable choice for use in antimicrobial prophylaxis in
all orthopaedic surgical procedure associated with a high
risk of infection due to Gram-positive bacteria,
particularly methicillin-resistant strains of S. aureus and S.
epidermidis.
Acknowledgements
The authors wish to thank both Ian Harding of Micron
Research Ltd (Marmont Priory Farm, Wisbech, UK) for
his contribution in providing clinical data from the three
studies monitored by Marion Merrell Dow, and Professor
Vieri Boddi of the Istituto di Patologia Generale,
University of Florence, for his contribution to the
statistical analysis of the data.
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Received 16 April 1997; returned 24 July 1997; revised 6
November 1997; accepted 24 November 1997
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