Zimmerli W, Widmer AF, Blatter M, Frei R, Ochsner PE, for the Foreign-Body Infection (FBI) Study Group . Role of Rifampin for Treatment of Orthopedic Implant–Related Staphylococcal Infections A Randomized Controlled Trial. JAMA. 1998;279(19):1537-1541. doi:10.1001/jama.279.19.1537
From the Division of Infectious Diseases, Department of Internal Medicine (Drs Zimmerli and Blatter), Division of Clinical Epidemiology (Dr Widmer), and Bacteriology Laboratory (Dr Frei), University Hospitals, Basel, Switzerland; and Clinic of Orthopedic Surgery, Kantonsspital, Liestal, Switzerland (Dr Ochsner).
Rifampin-containing regimens are able to cure staphylococcal implant-related
infections based on in vitro and in vivo observations. However, this evidence
has not been proven by a controlled clinical trial.
To evaluate the clinical efficacy of a rifampin combination in staphylococcal
infections associated with stable orthopedic devices.
A randomized, placebo-controlled, double-blind trial conducted from
1992 through 1997.
Two infectious disease services in tertiary care centers in collaboration
with 5 orthopedic surgeons in Switzerland.
A total of 33 patients with culture-proven staphylococcal infection
associated with stable orthopedic implants and with a short duration of symptoms
of infection (exclusion limit <1 year; actual experience 0-21 days).
Initial debridement and 2-week intravenous course of flucloxacillin
or vancomycin with rifampin or placebo, followed by either ciprofloxacin-rifampin
or ciprofloxacin-placebo long-term therapy.
Main Outcome Measures.—
Cure was defined as (1) lack of clinical signs and symptoms of infection,
(2) C-reactive protein level less than 5 mg/L, and (3) absence of radiological
signs of loosening or infection at the final follow-up visit at 24 months.
Failure was defined as (1) persisting clinical and/or laboratory signs of
infection or (2) persisting or new isolation of the initial microorganism.
A total of 18 patients were allocated to ciprofloxacin-rifampin and
15 patients to the ciprofloxacin-placebo combination. Twenty-four patients
fully completed the trial with a follow-up of 35 and 33 months. The cure rate
was 12 (100%) of 12 in the ciprofloxacin-rifampin group compared with 7 (58%)
of 12 in the ciprofloxacin-placebo group (P=.02).
Nine of 33 patients dropped out due to adverse events (n=6), noncompliance
(n=1), or protocol violation (n=2). Seven of the 9 patients who dropped out
were subsequently treated with rifampin combinations, and 5 of them were cured
without removal of the device.
Among patients with stable implants, short duration of infection, and
initial debridement, patients able to tolerate long-term (3-6 months) therapy
with rifampin-ciprofloxacin experienced cure of the infection without removal
of the implant.
ORTHOPEDIC DEVICES are used for bone fixation or joint replacement.
Orthopedic device–related infections are rare, but they carry a high
morbidity for the patient and are costly.1- 6
Traditionally, the management of such infections includes resection arthroplasty
or removal of fixation devices.1,3,4,7
Observational studies showed that despite prolonged (4-6 weeks) intravenous
treatment with β-lactam antibiotics and subsequent long-term oral therapy,
the failure rate with retention of the device is between 32% and 82%.8- 16
Among the best results are those of Tsukayama et al,8
who reported a failure rate of only 13 (32%) of 41 devices in patients with
early postoperative and hematogenous infection after hip arthroplasty. However,
in this study the polyethylene insert of the acetabular component was replaced
in all patients. High failure rates (69%-77%) were reported in 3 series.10,14,16 In these studies,
risk factors for failure were a long history of infection and a delayed debridement.
Osteomyelitis associated with fracture fixation devices occurs more
frequently than infection after joint replacement.5,6,17,18
The incidence of infection after internal fixation of closed fractures should
not exceed 1% to 2%, whereas the infection of open fractures can be higher
than 30% depending on the type of fracture.5,6,19
The treatment of infected bone fixation devices usually requires device removal
and stabilization with an external fixation device. The success rate of Staphylococcus aureus device–related infection with
a quinolone was only 20% (1/5) despite treatment for 6 months.20
Hitherto, there is not a single controlled, randomized clinical trial
evaluating the value of the antibiotic treatment of orthopedic device–related
infection. In most studies, only surgical procedures, not antimicrobial therapies,
are described.4- 18,21
Results from our animal model for implant-associated infection demonstrated
the clear superiority of rifampin combinations.22- 25
In addition, a prospective pilot study showed the success rate of rifampin
combinations in orthopedic implant–associated staphylococcal infections
to be 82% (9/11).26 These results were confirmed
in a larger series showing a success rate with ofloxacin plus rifampin of
62% (13/21) without removal of the device.27
Our study question was to estimate the cure rate of a conservative approach
with a controlled trial. Therefore, we conducted this double-blind, randomized
clinical trial evaluating the role of rifampin in patients with a stable orthopedic
implant infected with S aureus or coagulase-negative
Eligible for this study were patients who had a diagnosis of orthopedic
device–related infection due to S aureus or
coagulase-negative staphylococci established by arthrocentesis or surgical
revision. Only subjects in whom the stable implant was kept in place were
included. All consecutive patients treated by the infectious diseases consultants
of the study centers were asked to participate in the study. The following
exclusion criteria were applied: lack of written informed consent, symptoms
for more than 1 year before randomization, age younger than 16 years, less
than 2 years of expected survival, predictable inability to comply with the
treatment and follow-up visits, known or suspected allergy to quinolones and/or
rifampin, mixed infection with microorganisms other than staphylococci, staphylococci
resistant to ciprofloxacin and/or rifampin, removal of the implant before
randomization, clinical or radiological signs of implant loosening, refusal
to discontinue wearing soft contact lenses during treatment period, refusal
to discontinue hormonal contraception during treatment period, and an antimicrobial
treatment of more than 2 weeks after the microbiologically established diagnosis.
In addition, patients who took less than 85% of the study medication were
excluded a posteriori (poor compliance) and were regarded as dropouts. Patients
were randomly assigned to antimicrobial combination treatment (see below)
either with rifampin or with placebo, using a computer-generated list distributed
to the study centers in sealed envelopes. Patients were randomized by blocks
of 4, stratified into groups of patients with knee protheses, hip protheses,
or fixation devices. The study was approved by the local ethics committees
of the University Hospitals, Basel and Geneva, Switzerland. Written informed
consent was required for all study patients.
The patients were clinically assessed at enrollment in the study, at
weeks 1 and 2, then once monthly to month 6, then at 9, 12, and 24 months,
or until failure of the treatment or death of the patient. All patients including
dropouts were scheduled for a final evaluation at the end of the study. Radiological
evaluation was performed at study enrollment, after 1 and 2 years, or on removal
of the device. During treatment, the following laboratory parameters were
determined at least twice a month: C-reactive protein, hemoglobin, erythrocytes,
platelets, differential white blood cell count, and liver enzymes.
At study entry, any type of revision surgery was encouraged except the
removal of the device (exclusion criteria). Only cases with radiological (n=33)
and intraoperative (n=29) evidence of stability of the implant or the prosthesis
were included in the study. Fifteen cases in the rifampin group and 14 in
the placebo group had revision surgery for infection. At the revision, implants
were left in place (inclusion criteria). Thorough debridement was followed
by suction irrigation drainage or drainage alone. In osteosynthesis cases,
open-wound therapy was allowed as an alternative. There was no case where
gentamicin beads were used.
During the initial 2 weeks, patients were treated with flucloxacillin
(2 g every 6 hours intravenously) or, in case of methicillin resistance or
an allergy to penicillin, with vancomycin (1 g every 12 hours intravenously)
plus either rifampin (1 coated 450-mg tablet every 12 hours) or placebo (1
matched coated tablet every 12 hours). This initial 2-week course with a standard
intravenous treatment was chosen to minimize the risk of emergence of ciprofloxacin
resistance. An oral form of rifampin and an identical placebo was provided
by Ciba-Geigy Ltd, Basel, Switzerland. Patients were informed that body fluids
can turn orange with placebo or drug. After 2 weeks, flucloxacillin or vancomycin
was replaced by ciprofloxacin (750 mg every 12 hours by mouth), whereas the
rifampin or placebo was continued. Patients with hip prostheses and internal
fixation devices were treated for 3 months, those with knee prostheses for
6 months. After this time, antimicrobial treatment had to be stopped if the
patient had no clinical signs and symptoms of infection and the C-reactive
protein level was below 5 mg/L for at least 6 weeks. The surgeon was encouraged
to remove osteosynthesis material after stopping antimicrobial therapy for
at least 1 week, provided that the material was no longer required for stability.
The whole implant was sent to the microbiology laboratory. Identification
of the same microorganism was considered as failure.
Cure was defined as the lack of clinical signs
and symptoms of infection (fever, local pain, redness, warmth, sinus tract
infection, fever), a C-reactive protein level below 5 mg/L, and the absence
of radiological signs of loosening, pseudoarthrosis (in case of fixation device),
or dislocation of the artificial joint at the final follow-up visit 24 months
after start of the treatment. In case of the removal of the internal fixation
device because of sufficient stability, cure was
defined as the absence of the infecting agent of the cultured implant. For
this purpose, the entire device was cultured in trypticase soy broth and sonicated
in case of no growth after 48 hours of incubation. Sonication was delayed
since gram-negative microorganisms could be killed by sonication and superinfection
could therefore be missed. Confirmed failure was
defined as isolation of the initial microorganism (persistence or relapse)
in the culture of intraoperative tissue specimens, synovia, or device. A probable failure was defined as clinical signs and symptoms
of local infection, or an otherwise unexplained high C-reactive protein level
(>50 mg/L) without microbiological documentation of infection.
The isolates were identified by standard techniques.28
Minimal inhibitory concentrations of the study drugs were determined by E-test
(AB BIODISKA, Solna, Sweden) at the principal study center. All isolates were
collected and stored in skim milk at −70°C for molecular typing
in case of treatment failure. For this purpose, pairs of isolates were characterized
by the contour-clamped homogenous electrical fields modification of pulsed-field
gel electrophoresis, after digestion of chromosomal DNA with low-frequency
cutting enzymes (SmaI and Eag
Cure rates of orthopedic device–related infections with the standard
regimen range from 20% to 30% without removal of the device.10,12,14,16
Experimental data and uncontrolled case series with rifampin combinations
indicated a cure rate between 70% and 90%.26,27
The sample size was calculated with the following assumptions: α was
set at .05, the power at 80%, the probability of cure with standard treatment
at 20%, and the probability of cure with study treatment at 75%. A sample
size of more than 30 subjects was calculated, with an estimated dropout rate
Time to failure was estimated with the Kaplan-Meier method, and compared
between groups by the log-rank test.31 Categorical
variables were compared by the χ2test or the Fisher exact test.
The independent safety monitor was the only one who was aware of the type
of blinded study drug. A P value of <.05 (2-tailed)
was considered significant.
Patients enrollment started in May 1992, and the last follow-up visit
was performed in November 1997, or at the removal of the device if failure
occurred. After randomization of 33 patients, the investigators were asked
by the safety advisor to stop randomization because all failures occurred
in the same group.
The 2 groups were similar in demographic characteristics, type of devices,
and infecting agents (Table 1).
In the rifampin combination group, 12 of the 18 infections occurred within
2 months after implantation of the device, compared with 7 of the 15 in the
placebo combination group. However, the duration of infectious signs and symptoms
was short and similar in both groups, ie, all infections occurred either early
after intraoperative contamination (<2 months) or late as a consequence
of hematogenous seeding (Table 1).
Twenty-four patients fully completed the trial and 9 dropped out for various
reasons but received further follow-up (see below).
Figure 1 shows the Kaplan-Meier
plot of disease-free survival in the 24 patients who completed the study according
to the protocol. The cure rate was 12 (100%) of 12 in the rifampin combination
arm, and 7 (58%) of 12 in the placebo combination arm, with a median follow-up
of 35 (range, 24-46 months) and 33 (range, 15-41 months) months, respectively.
The definite proof for cure of a device-related infection is the negative
broth culture of the whole explanted foreign body after antimicrobial therapy.23,24 This unambiguous test was performed
in 8 of the 10 patients with fixation devices in the ciprofloxacin-rifampin
group and in 2 of 6 patients in the ciprofloxacin-placebo group. In the former
group, all 8 implant cultures were negative; in the latter group, 1 of 2 implant
cultures showed growth of the initial pathogen. All 5 failures were microbiologically
confirmed (see below); all had flucloxacillin as the initial intravenous therapy.
We also performed an intention-to-treat analysis. Sixteen (89%) of the
18 patients of the rifampin combination arm and 9 (60%) of 15 patients of
the placebo combination arm were cured without removal of the implant before
the end of the antimicrobial therapy (P=.10). In
the 2 patients from the former group in whom treatment failed, rifampin therapy
was stopped after 8 weeks, in 1 patient due to an exanthema; in the other
patient, the dose of rifampin was reduced after 3 weeks because of nausea.
As expected for a long-term study, a considerable percentage of patients
dropped out. All dropouts had an identical follow-up observation as did the
treated patients. In the rifampin combination arm 6 of the 18 patients dropped
out, and in the placebo combination arm 3 of the 15 (P=.45, Table 2). In the rifampin combination arm,
in 3 patients rifampin therapy had to be temporarily discontinued due to severe
nausea, but could be continued within a few days with a reduced dose (300
mg every 12 hours). In 2 other patients, rifampin therapy was definitely stopped
due to an allergic exanthema. One patient dropped out due to protocol violation
because the orthopedic surgeon did not agree to stop therapy at the required
time point according to the study protocol.
In the placebo combination arm, reasons for dropping out were an adverse
event (nausea), noncompliance, and a protocol violation. Seven of 9 dropout
patients were subsequently treated withrifampin combinations, 3 of them with
a reduced dose. The success rate among the rifampin-treated dropout patients
of both groups together was 5 (71%) of 7 without removal of the device during
antimicrobial therapy (Table 2).
Four methicillin-sensitive S aureus and 1 methicillin-sensitive S epidermidis isolates were cultured from the 5 failures
in the ciprofloxacin-placebo group. The isolates at failure were compared
with the initial isolates by susceptibility testing and molecular subtyping.
In 4 of these isolates (3 S aureus and 1 S epidermidis), the minimal inhibitory concentration of ciprofloxacin
increased 3- to 8-fold to 4 mg/L, and in 1 failure S aureus remained susceptible to ciprofloxacin. The analysis of the chromosomal
DNA of the ciprofloxacin-resistant strains by pulsed-field gel electrophoresis
showed identity of all bands, indicating emergence of quinolone resistance
during prolonged ciprofloxacin monotherapy of the pathogen isolated at randomization
We found a superiority of the rifampin combination regimen compared
with the ciprofloxacin monotherapy. Foreign bodies are favorite sites for
bacterial persistence due to a local host-defense defect.32
In addition, the biofilm and the low growth rate of surface-adherent microorganisms
render many antimicrobial agents ineffective.23,24,33,34
Therefore, most orthopedic surgeons remove all foreign material in case of
an infected arthroplasty.1,3,4,7
The superiority of rifampin in the animal model could be explained by its
high efficacy on adherent and stationary-phase staphylococci.23- 25
The excellent results of the rifampin combination in this study confirm previous
data from animal models and observational studies.22- 27
In addition, this combination has also been shown to be efficacious in right-sided
endocarditis due to S aureus.35,36
However, there are no controlled studies on the role of rifampin in nonmycobacterial
Our results confirm the high risk of emergence of resistance of staphylococci
to quinolones when used as monotherapy.37 Emergence
of resistance to rifampin was not observed in a single case in our study.
Recurrent infections were exclusively caused by the original strain, as confirmed
by molecular typing of both the original and consecutive isolates. This indicates
that bacteria may persist despite initial clinical response to antibiotic
treatment. Therefore, surface adhering staphylococci seem to be highly resistant
even to prolonged quinolone monotherapy, as previously suggested by animal
experiments and observational studies.20,23,24
The present study shows that the rifampin-quinolone combination was highly
efficacious, not only in eliminating device-associated staphylococci, but
also in preventing the emergence of ciprofloxacin resistance.
Our results cannot be generalized to every type of orthopedic implant–associated
infection. According to the inclusion criteria, all devices were stable. Loosening
of the infected device precludes an antimicrobial therapy without removing
or exchanging the implant.4 Despite the fact
that we allowed the inclusion of patients with up to 1 year of infection,
the median duration of signs and symptoms of infection was only 4 and 5 days,
respectively, with a maximum of 21 days. According to Schoifet and Morrey,10 the long duration of the infection before debridement
is the major cause of treatment failure. However, in these studies, the antibiotic
therapy was not standardized and did not include rifampin. Nevertheless, it
is conceivable that the treatment with retention is only successful in patients
with a short interval before therapy. In our study, only patients with early
(<2 months after surgery) or acute hematogenous infection were treated.
Therefore, we can only speculate that patients with chronic orthopedic device–related
infections can also be successfully treated with ciprofloxacin plus rifampin
with retention of the device.
Dropouts were mainly observed in the combination treatment group. All
dropout patients had an identical follow-up as the other cases. Seven dropout
patients were subsequently treated with rifampin combinations, 3 of them with
a reduced dose due to nausea as the main adverse event. Six of 7 rifampin-treated
patients had a successful outcome, 5 of them without removal of the device—supporting
the main conclusion. Compliance was excellent in both groups as checked by
pill counting. Only 1 patient dropped out due to insufficient compliance (<85%
of the study medication).
This is the first randomized, controlled clinical trial evaluating a
conservative treatment approach to staphylococcal device–related infection
with rifampin. It confirms the in vitro and experimental animal data,23- 25 as well as the results
of observational clinical studies.26,27
In conclusion, orthopedic device–related infections due to rifampin-
and ciprofloxacin-susceptible staphylococci can be cured without removal of
the device, given the implant is stable, the duration of infection is short,
an initial debridement is performed, and the patient tolerates long-term therapy.