1. No category

International Journal of Infectious Diseases (2005) 9, 127—138
http://intl.elsevierhealth.com/journals/ijid
REVIEW
Antibiotic treatment of osteomyelitis: what have
we learned from 30 years of clinical trials?
Luca Lazzarini a,*, Benjamin A. Lipsky b, Jon T. Mader c,ä
a
Department of Infectious Diseases and Tropical Medicine, S. Bortolo Hospital, 36100 Vicenza, Italy
Medical Service, and Antibiotic Research Clinic, VA Puget Sound Health Care System
and Department of Medicine University of Washington, Seattle, WA, USA
c
Department of Orthopaedics and Rehabilitation, Department of Infectious Diseases,
University of Texas Medical Branch, Galveston, TX, USA
b
Received 12 January 2004; received in revised form 1 July 2004; accepted 29 September 2004
Corresponding Editor: Marguerite Neill, Pawtucket, USA
KEYWORDS
Osteomyelitis;
Infection;
Bone;
Antibiotic;
Therapy;
Treatment
Summary
Objectives and design: To determine the most appropriate approach to antibiotic
therapy for osteomyelitis, the medical literature for articles published from 1968 to
2000 was reviewed.
Results: Ninety-three clinical trials in children and adults were identified using
almost every antibiotic class. Most studies were non-comparative and the comparative trials involved relatively few patients. Publications generally did not provide
clinically important information regarding infection staging or classification, surgical
treatment provided, or the presence of orthopedic hardware. The median duration of
follow-up after treatment was only 12 months.
The clinical outcome was better for acute than chronic osteomyelitis in eight of the
12 studies allowing comparison. In the comparative trials, few statistically significant
differences were observed between the tested treatments. In one small trial, the
combination of nafcillin plus rifampin was more effective than nafcillin alone. In
pediatric osteomyelitis, oral therapy with cloxacillin was more effective than tetracycline in one study, and oral clindamycin was as effective as parenteral antistaphylococcal penicillins in another. In several investigations oral fluoroquinolones
were as effective as standard parenteral treatments.
Conclusions: Although the optimal duration of antibiotic therapy remains undefined,
most investigators treated patients for about six weeks. Despite three decades of
research, the available literature on the treatment of osteomyelitis is inadequate to
determine the best agent(s), route, or duration of antibiotic therapy.
# 2005 International Society for Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.
* Corresponding author. Tel.: +390444993998; fax: +390444993616.
E-mail address: [email protected] (L. Lazzarini).
ä
Deceased.
1201-9712/$30.00 # 2005 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ijid.2004.09.009
128
Introduction
The introduction of antibiotics for treating bacterial
infections revolutionized the natural history of
many of these common and deadly diseases. In
the first decades of the antibiotic era, the remarkable clinical successes with antibiotics led to an
atmosphere of optimism. Based upon these early
successes, Florey and Florey believed that osteomyelitis, if treated with antibiotics early, would no
longer be a surgical condition.1 With a mounting
record of clinical failures, however, this optimism
vanished within a few years. By 1968, Bick’s book
reviewing 25 years of experience with antibiotic
treatment led him to conclude that it was invaluable
for eliminating osteomyelitis-related septicemia
and abscesses, but that chronic bone infection could
only be cured with surgery.2
Today, most authorities still believe that chronic
osteomyelitis generally requires both antibiotic and
surgical treatment.3 But, despite continued
research, most aspects of antibiotic treatment for
osteomyelitis are still poorly understood. Data are
sparse about which are the most effective antimicrobial agents, for how long, and by what routes
they should be administered for various types of
osteomyelitis. Animal models have been useful in
studying this complex disease, but they cannot
replicate many aspects of human bone infection.4
Thus, the treatment of osteomyelitis is still mostly
based on expert opinions, and no consensus guidelines are currently available. Many human trials on
treating osteomyelitis in the last 30 years have been
published, but only the randomized ones have been
systematically reviewed. To supplement the data
from randomized trials with those of non-controlled
trials, the most relevant studies of antibiotic therapy of human osteomyelitis published between 1968
and 2000 are reviewed here.
Materials and methods
All clinical studies investigating antibiotic treatment
of osteomyelitis were searched by means of the MEDLINE search engine (National Library of Medicine,
Washington, DC, USA), applying no language limitation. The terms ‘antibiotic’, ‘antimicrobial’, ‘therapy’, ‘treatment’, ‘bone’, and ‘osteomyelitis’ were
used as keywords in various combinations. Studies
were found that enrolled both pediatric and adult
cases of osteomyelitis, recognizing that the former
are more often hematogenous and the latter more
often contiguous infections. While there are other
commonly used methods of treating osteomyelitis,
e.g., local administration of antibiotics by beads, this
L. Lazzarini et al.
review was aimed exclusively at systemic antibiotic
therapy.
After reading the abstracts of all retrieved articles, 120 papers published between January 1968
and January 2001 were identified as possibly being
clinical trials. Trials were selected for analysis only
when they met all of the following criteria: (1) more
than six cases of osteomyelitis were treated; (2)
data about the clinical outcome of the infections
were available; and, (3) a single drug or class of
drugs was used, or, in the case of comparative
studies, in at least one arm of the study. Studies
about ‘bone and joint infections’, or infections
other than osteomyelitis (such as endocarditis,
meningitis) were included only if separate data
about the outcome of bone infection were provided.
Patients identified as having prosthetic joint infections or infected orthopedic hardware or implants
were not included because these infections generally require surgical interventions and do not
respond to antibiotic therapy alone. The criterion
for requiring at least six treated cases was arbitrarily selected by the authors to avoid considering
small anecdotal studies and because one potentially
relevant comparative trial included only six patients
per arm. Of the 123 papers initially identified, it was
not possible to obtain three of them despite
requests to an inter-library loan service, five were
discarded because they were review articles rather
than clinical trials, five because they pooled the
outcome of different musculoskeletal infections,
five because they enrolled less than six cases of
osteomyelitis, four because of incomplete outcome
data, and seven because they utilized many different antibiotics and pooled the outcome of all the
patients.
For each study the following were recorded: the
study design, criteria for diagnosis of osteomyelitis
(clinical, microbiological, radiological, histological), name(s) of the antibiotic(s) used, mean age
and sex of the patients, number of pediatric
patients, number of cases treated, number of cases
of long bone osteomyelitis, use of a classification
system, presence of orthopedic hardware and
whether or not it was removed, bone culture isolates, duration of antibiotic treatment, occurrence
of side effects requiring treatment discontinuation,
antibiotic levels in serum and bone, number of
patients undergoing surgery, treatment outcome,
explanation for failure given by the authors, and
duration of follow-up after treatment.
Data were analyzed by means of statistical software (Epi Info 2000, Centers for Disease Control and
Prevention, Atlanta, GA, USA). Because different
definitions of outcome were used in the studies
reviewed, the authors devised their own. For each
Antibiotic treatment of osteomyelitis
129
study outcomes were defined as follows: ‘cure’ was
the absence of clinical evidence of osteomyelitis
after the follow-up period; ‘failure’ was any outcome not fulfilling the criteria for ‘cure’. Discontinuation of treatment due to side effects of the study
drug was considered separately.
Results
Study features and overall population
enrolled
This review uncovered 93 studies that fulfilled the
selection criteria, with a total of 2476 cases of osteomyelitis.5—97 Among these, 17 studies (18%) were
comparative, ten of which were randomized; the
other 76 were non-comparative. In the studies providing this information, 1090 patients (44%) were
male, and the mean age was 42 years (range 5—66
years, 12.2 [SD]). The mean number of patients
enrolled per study was 26 (range 6—169, 24.5
[SD]); 483 of the cases were pediatric osteomyelitis
and 603 were long bone osteomyelitis.
The authors diagnosed osteomyelitis by various
combinations of clinical, radiological and microbiological findings in 29 studies. The generally accepted
standard criterion for diagnosis, a bone biopsy for
microbiology, was mandatory in only 24 studies, four
of which also required a histological diagnosis. Four
studies required clinical, microbiological, and radiological criteria, whereas in seven studies either
compatible clinical and microbiological criteria, or
microbiological and radiological criteria, were sufficient. Five other studies required just clinical and
radiological criteria, not microbiological confirmation. No criteria for diagnosis were specified in 24
studies.
A classification of the type of osteomyelitis was
provided in 45 (48%) of the studies; ‘acute or
chronic’ was used in 44, the Cierny—Mader classification3 was used in one, and a radiological classification was used in one. Information about hardware
implantation was available in 12 studies (89
patients) and information about hardware removal
was provided in 11 studies (17 patients). Data about
the duration of the antibiotic treatment were available in 88 studies; in these, the mean duration of
treatment was 51 days and the median duration of
treatment was 40 days (range 6—180 days, 42.29
[SD]). Serum and bone antibiotic levels were measured in 32 and 11 studies, respectively. Information
about surgical treatment for osteomyelitis was
available in 27 studies, involving 455 patients. Dura-
Table 1 Major findings of the studies using anti-staphylococcal penicillins for the treatment of staphylococcal
osteomyelitis.
Author (ref)
Drug(s)
Duration of
treatment
in weeks
Duration
of follow-up
in months
Number
of cured
patients/total
Severe
adverse
events
Norden*5
Nafcillin iv vs
nafcillin iv + rifampin po
6
6
no
Norden*6
Nafcillin iv vs
nafcillin iv + rifampin po
6
24
Leder7
Bell8
Flucloxacillin, continuous iv infusion
Cloxacillin po or dicloxacillin po
6
24
15
7—30
7/8
6/7
c
2/8
8/10
c
9/11
18/19
Hodgkin9
Bryson10
Cloxacillin po or dicloxacillin po
Dicloxacillin po
24
6
17
60
Cole11
Hubbard*12
Cloxacillin po
Cloxacillin po
vs tetracycline po
6
4
24
NA
Hedstrom*13
Cloxacillin po
vs dicloxacillin po
24
NA
9/14
18/18
ch
53/64 (83%)
14/27
2/19
ch,c
4/6
6/6
ch, ad
no
no
1 allergic
reaction
2 hepatotoxicity
no
no
no
1 with
dicloxacillin
*: Comparative trial; GPC: Gram-positive cocci; GNR: Gram-negative rods; ad: adult; ch: children; c: chronic osteomyelitis; a:
acute osteomyelitis; iv: intravenous; im: intramuscular; po: oral; Unless otherwise specified, the studies involved adult
osteomyelitis.
130
L. Lazzarini et al.
Table 2 Major findings of the studies of beta-lactam/beta-lactamase inhibitor combinations, carbapenems and
monobactams for treating osteomyelitis.
Author (ref)
Drug(s)
Commonest
microorganism(s)
Duration of
treatment
(weeks)
Duration of
follow up
(months)
Number
of cured
patients/total
(%)
Severe side
effects
Gentry14
Ticarcillin-clavulanic
acid iv
Ticarcillin-clavulanic
acid iv
GPC
4
9
22/36 (61)
S. aureus
NA
8/8
S. aureus
22
5/9
no
NA
4—6
NA
4/8
24/27 (89)
no
GPC
2—6
NA
GPC and GNR
NA
36
GPC and GNR
4
6
Giamarellou25
Greenberg26
Scully27
Prybil28
Simons29
Conrad29
Ticarcillin-clavulanic
acid iv
vs moxalactam iv
Ticarcillin-clavulanic
acid iv
Ampicillin-sulbactam
iv vs clindamycin po
Ampicillin-sulbactam
iv vs cefotaxime iv
Ampicillin-sulbactam
iv vs ceftriaxone iv
Aztreonam iv
Aztreonam iv
Aztreonam iv
Aztreonam iv
Aztreonam iv
Aztreonam iv
1 (followed
by 4 weeks
with other
oral drugs)
4
2 (bleeding,
urticaria)
no
GNR
GNR
P. aeruginosa
P. aeruginosa
P. aeruginosa
P. aeruginosa
10
3—15
6—15
1
12
6
Mogabgab30
MacGregor31
Moxalactam iv
Imipenem iv
6
4
NA
3
2
4a
6c
4
4
Jacobs15
Siebert*16
Johnson17
Reinhardt*18
Loffler*19
Kulhanjian*20
GPC and GNR
GPC and GNR
NA
11
2/10
1/3
5/5
3/5
5/5
4/4
4/7
8/9
5/9
13/16
11/11
5/6 a
12/12 c
7/8
20/34 (59)
no
no
no
no
no
no
no
no
no
no
*: Comparative trial; GPC: Gram-positive cocci; GNR: Gram-negative rods; ad: adult; ch: children; c: chronic osteomyelitis; a:
acute osteomyelitis; iv: intravenous; im: intramuscular; po: oral; Unless otherwise specified, the studies involved adult
osteomyelitis.
tion of follow-up was explicit in 73 studies, the mean
being 16.6 months (range 1—67 months, median 12).
In 12 studies, the outcome of acute and chronic
cases of osteomyelitis was detailed separately. In
eight (67%) of these studies patients with acute
osteomyelitis achieved a higher cure rate than
patients with chronic osteomyelitis, in three studies
outcome was better in patients with chronic osteomyelitis, and in one study the outcome was similar in
each type. These differences were not statistically
significant in any single study.
(Table 2). There were 30 trials investigating cephalosporins, ranging from first generation agents in the
late 1970s to fourth generation agents in the 1990s
(Table 3). Among glycopeptides, teicoplanin was
used in seven studies and vancomycin was administered by continuous infusion in one study33
(Table 4). Fluoroquinolones were used in 16 noncomparative and six comparative trials (Table 5).
Finally, the results of trials of miscellaneous antibiotics are reported in Table 6. The pertinent details
of all trials are shown in the tables.
Studies by type of antibiotic therapy
Discussion
Three studies were found that used intravenous
antistaphylococcal penicillins and six studies with
oral antistaphylococcal penicillins (Table 1). Seven
trials investigated a beta-lactam/beta-lactamase
inhibitor, aztreonam was used in six trials, moxalactam and imipenem/cilastatin in one study each
Osteomyelitis is a relatively common infection, but
a surprisingly small number of comparative trials
about its treatment have been published. Moreover,
most of the studies involve relatively few patients
and are not randomized. The aim of these trials was
Antibiotic treatment of osteomyelitis
131
Table 3 Major findings of the studies using cephalosporins for treating osteomyelitis.
Commonest
microorganism(s)
Severe
Duration of Duration of Number
adverse
treatment follow-up of cured
in months patients/total events
in weeks
(%)
Author (ref)
Drug(s)
Arango46
Fass47
Liu48
Schurman49
Levine50
Bernstein51
Cefazolin im(a)
S. aureus
or cephapirin im (c)
Cefazolin iv
S. aureus
Cefoxitin iv
GPC and GNR
Cefoxitin iv
GPC and GNR
Cefamandole iv
S. aureus
Cefamandole iv
S. aureus
4—7 a
24 c
4
2
2
3
4
13
NA
6
NA
5—23
Levine52
Cefamandole iv
S. aureus
4
NA
LeFrock53
Nelson54
S. aureus
S. aureus
4
3
NA
NA
12/12
22/23 (96)
Temple55
Biehl56
LeFrock57
Cefamandole iv
Cefamandole iv
and cefaclor
(sequentially)
Cefoperazone iv
Cefoperazone iv
Cefotaxime iv
NA
S. aureus
GPC
4
1
3
NA
NA
NA
Mader58
Cefotaxime iv
S. aureus
4
12
Mader59
Cefotaxime iv
S. aureus
6
6a
7c
7/9
18/24
6/7 a
25/32
23/25
24/27
21/22
38/46
LeFrock60
Cefotaxime iv
GPC
4
12—24
Jacobs61
Mader62
Gomis63
Dutoy64
Cefotaxime iv
Ceftizoxime iv
Cefotaxime iv
Ceftazidime iv
GPC
GPC and GNR
E. coli
P. aeruginosa
2
6
4
4
NA
1—12
6
6
Eron65
Bach66
Ceftazidime iv
Ceftazidime iv
P. aeruginosa
P. aeruginosa
6
4
De Bastiani67
Giamarellou68
Yogev69
Pottage70
Routman71
Lucht72
Sheftel73
Jauregui74
Kunkel75
Ceftazidime iv
Ceftriaxone iv
Ceftriaxone iv
Cefsulodin iv
Cefsulodin iv
Cefsulodin iv
Cefmenoxime iv
Cefepime iv
Cefonicid iv
or im
GPC and GNR
4
NA
3
GPC and GNR
4
P. aeruginosa
4
P. aeruginosa
24
P. aeruginosa
24
GPC
6
S. aureus, GPC, and GNR 4
S. aureus
6
NA
6a
12 c
12—48
NA
2
12
12
36
12
12
3—13
6
8/20 a (40)
7/10 c
12/13
8/8
6/9
14/16
5/5 a
5/9 c
20/25 a (80)
22/25 c (88)
1
NA
separately for
osteomyelitis
0
(75)
c
a
c
a
c
(78)
(92)
(89)
(96)
(83)
12/12 a
17/20 c (85)
23/24 (96)
13/14
40/50 (80)
7/7 a
11/14 c
4/8
9/11 a
7/15 c
9/10
3/7
6/6
3/8
12/16
11/15
6/15
19/23 (83)
12/12
2 neutropenia
at end of
treatment
4
1 leukopenia
3
*: Comparative trial; GPC: Gram-positive cocci; GNR: Gram-negative rods; ad: adult; ch: children; c: chronic osteomyelitis; a:
acute osteomyelitis; iv: intravenous; im: intramuscular; po: oral; Unless otherwise specified, the studies involved adult
osteomyelitis.
generally to determine if a ‘new’ drug was at least
equivalent to an established treatment, in order to
justify using it for treating bone infections. Most of
the trials failed to detect statistically significant
differences between the two groups, thus providing
little understanding about the relative effectiveness of various regimens for treating osteomyelitis.
Another limitation of the available literature is that
trials involving ‘bone and joint infections’ include a
heterogeneous spectrum of diseases, with different
132
L. Lazzarini et al.
Table 4 Major findings of the studies using glycopeptides for treating staphylococcal osteomyelitis.
Author (ref)
Drug(s)
Duration of
treatment
(weeks)
Duration of
follow-up
(months)
Number of
cured
patients/total
(%)
Severe
adverse
events
Bernard33
Vancomycin, iv
continuous infusion
Teicoplanin iv
Teicoplanin iv
Teicoplanin iv
Teicoplanin iv
24
14
10/15
no
NA
NA
6
6
3
12
12
6
6/8
2/7
10/14
3/14 a
8/20 c (40)
18/44 (41)
no
no
no
no
76/80 a (95)
62/65 c (95)
72/76 (95)
24 patients
de Lalla34
Marone35
Greenberg36
Weinberg37
Graninger38
8
12
LeFrock39
Teicoplanin iv,
three times weekly
Teicoplanin iv
6
6
Testore40
Teicoplanin im
24
12
no
no
*: Comparative trial; GPC: Gram-positive cocci; GNR: Gram-negative rods; ad: adult; ch: children; c: chronic osteomyelitis; a:
acute osteomyelitis; iv: intravenous; im: intramuscular; po: oral; Unless otherwise specified, the studies involved adult
osteomyelitis.
prognoses. For example, the cure rate with antibiotics alone of pediatric hematogenous osteomyelitis is much higher than that of a prosthetic joint
infection. Thus, in this review only studies that
provided separate outcomes for patients with osteomyelitis are included. Moreover, to avoid anecdotal
information, trials involving fewer than six patients
were excluded. Finally, it has been noted that studies reporting poor outcomes may be less likely to be
published, introducing the possibility of publication
bias. While an exhaustive literature search was not
performed, it is believed that these methods are
likely to have revealed the best quality published
papers. The similarity of the reported cure rates for
the various studies suggests that the results are
likely to be accurate and generalizable.
Taking into account all the variables in patients
with osteomyelitis (e.g., pathogenesis, localization,
microbial etiology, surgical treatment) would
require analyzing a large number of cases. A recent
systematic review of the use of antibiotics for
treating bone and joint infection98 included only
controlled trials, but did not separate patients
with bone versus joint infections. The authors
concluded that there is little high quality evidence
on the relative effectiveness of various regimens
of antibiotic therapy for osteomyelitis or septic
arthritis. Furthermore, by excluding uncontrolled
studies, they ignored most of the trials on osteomyelitis. In this literature review, 82% of the published osteomyelitis studies were non-comparative.
Thus, to capture all of the available data, both
comparative and non-comparative studies have
been reviewed.
Another problem for studies on osteomyelitis is
that of defining the outcome. Virtually every study
offered a different definition, using terms such as
‘cure’, ‘improvement’, ‘eradication’, ‘failure’, and
‘recurrence’, each having a different meaning.
Using the Infectious Disease Society of America
(IDSA) guidelines on the requirements of human
trials on osteomyelitis,99 a common definition was
adopted that reflects what can be expected from a
course of treatment with antibiotics: a favorable
outcome means that the patient is clinically free of
disease at the end of the follow-up period. Furthermore, clinical trials should have at least a one-year
follow-up period. Unfortunately, many studies did
not have this minimum follow-up. Moreover, the
duration of follow-up varied markedly, making it
difficult to compare data from different studies
on the same antibiotic.
Another problem is the disease classification
schemes used in the studies. About half of the
reviewed studies did not use any osteomyelitis classification system. In the others, the most commonly
used classification was simply ‘acute’ versus
‘chronic’. Unfortunately, most authors did not provide definitions of acute and chronic osteomyelitis
and when given, the threshold between acute and
chronic ranged from 20 days to six months. The
hallmark of chronic osteomyelitis is the presence
of necrosis on bone histology. Since this finding may
be present early on during the natural history of the
disease, classification into acute versus chronic by
duration of disease is inaccurate.100 Although several classifications of osteomyelitis have been advocated,100 none is universally accepted.
Antibiotic treatment of osteomyelitis
133
Table 5 Major findings of the studies using fluoroquinolones for treating osteomyelitis.
Severe
side
effects
Commonest
microorganism
(s)
Duration
Duration Number
of cured
of treatment of
follow-up patients/
total (%)
Non-comparative Trials:
Ramirez76
Ciprofloxacin po
Scully77
Ciprofloxacin po
Slama78
Ciprofloxacin po
Gilbert79
Ciprofloxacin po
Trexler Hessen80
Ciprofloxacin po
Gudiol81
Ciprofloxacin po
Lopez82
Ciprofloxacin po
Yamaguti83
Ciprofloxacin po
Dan84
Ciprofloxacin po
Mac Gregor85
Ciprofloxacin po
Ketterl86
Ofloxacin po
Kannellakopoulou87 Ofloxacin po
Eron88
Ofloxacin po
Liu89
Fleroxacin po
Dellamonica90
Oral fluoroquinolones
Greenberg91
Oral fluoroquinolones
GPC and GNR
P. aeruginosa
GNR
GNR
P. aeruginosa
NA
NA
GPC and GNR
P. aeruginosa
NA
S. aureus
GNR
GPC and GNR
NA
S. aureus
S. aureus
6
6
11
6—14
9
8
NA
23
12
20
3
24
24
4
24
8
NA
NA
NA
7—21
10
11
NA
12
27
18
6
6
12
3
36
12
5/8
0
4/6
0
22/30 (73) 0
13/20 (65) 0
22/24 (92) 2
15/20 (75) 0
1/8
13/17 (76)
19/22 (86)
11/18 (61) 1
113/115 (98)
15/20 (75)
6/6
4/7
29/39 (74)
16/27 (59) 3
Comparative Trials
Giamarellou*92
NA
25
12
7/8
Author (ref)
Drug
Pefloxacin iv or po vs
ceftazidime iv
Gentry*93
Ofloxacin po vs cefazolin Polymicrobial
iv or ceftazidime iv
8
18
5/6
14/19
Gomis*94
Ofloxacin po vs
Imipenem-cilastatin iv
NA
4
6
12/14
7/11
Gentry*95
Ciprofloxacin po vs
nafcillin po
S. aureus
7
12
7/10
24/31 (77)
Mader*96
Ciprofloxacin po vs
nafcillin iv +
clindamycin po
GPC
6
32
22/28 (79)
11/14
Greenberg*97
Ciprofloxacin po vs
parenteral treatments
Enterobacteriaceae 4
13
10/12
6/14
no
1
Imipenem
11/16
*: Comparative trial; GPC: Gram-positive cocci; GNR: Gram-negative rods; ad: adult; ch: children; c: chronic osteomyelitis; a:
acute osteomyelitis; iv: intravenous; im: intramuscular; po: oral; Unless otherwise specified, the studies involved adult
osteomyelitis.
Some studies were restricted to specific causative organisms, based on the spectrum of the study
drug. Most of infections were monomicrobial, but
cases of polymicrobial osteomyelitis occurred, especially associated with a diabetic foot infection.
Since it is not known if cases of osteomyelitis due
to different microbial species have different outcomes, it would probably be more accurate to
restrict antibiotic trials to a single microbial
species or category. Very few studies specified the
antimicrobial susceptibility patterns of the isolated
organisms, e.g., the prevalence of methicillin-resistant Staphylococcus aureus or Gram-negative
organisms with extended spectrum beta-lactamases.
Information about surgical treatment for osteomyelitis, and the presence of surgically implanted
bone hardware (and whether or not it was removed)
was not provided in most studies. These factors
greatly influence the outcome of treatment. Most
authorities believe that an incompletely debrided
bone infection is prone to treatment failure, no
134
L. Lazzarini et al.
Table 6 Major findings of the studies using miscellaneous antibiotics for treating osteomyelitis.
Author (ref)
Drug(s)
Commonest
microorganism(s)
Duration of
treatment
(weeks)
Duration of
follow-up
(months)
Number
of cured
patients/
total (%)
Severe
side
effects
Beauvais21
Feigin22
Pristinamycin po
Clindamycin po
S. aureus
S. aureus
18
24
Clindamycin po
Clindamycin po,
vs nafcillin iv
Cotrimoxazole po
vs oral penicillins
Cotrimoxazole po
+ rifampin po
Fosfomycin po
Fusidic acid po
Fusidic acid po
S. aureus
S. aureus
S. aureus
4—8
12
S. aureus
4
43
25/31 (81) ch
13/19 a
6/6 ch
28/29 (97) ch
11/12
9/13
30/66 (45)
22/45 (49)
21/27 (78)
6 patients
no
Rodriguez23
Kaplan24
6—12
6a
24 c
10
6
S. aureus
S. aureus
Coagulase
negative
staphylococci
3
NA
3
48
NA
NA
29/37 (78)
54/72 (75)
19/20 (95)
Saengnipanthkul41
Sanchez42
Fernandez43
Hierolzer44
Coombs45
15
12
1 allergy
no
no
3
no
no
no
*: Comparative trial; GPC: Gram-positive cocci; GNR: Gram-negative rods; ad: adult; ch: children; c: chronic osteomyelitis; a:
acute osteomyelitis; iv: intravenous; im: intramuscular; po: oral; Unless otherwise specified, the studies involved adult
osteomyelitis.
matter what antibiotic therapy has been
used.3,100,103 Radical debridement of infected or
necrotic bone is even more important in the
compromised host.101 Therefore, information is
req-uired about any surgical treatment provided
in a study about antibiotic treatment of osteomyelitis.
Duration of antibiotic therapy is also an important issue when treating osteomyelitis. There is
little published evidence upon which to determine
the most effective duration. In the reviewed papers
two major trends were found: most treated the
patients for about six weeks, while a minority treated patients for about six months. Data from animal
models show that bacteria can be cultured from
infected bone even after two weeks of appropriate
antibiotic therapy;102 therefore, treatment for four
to six weeks has usually been advised.3,103 One
retrospective survey of clinical cases supported a
shorter duration of treatment;104 there is no published evidence of better results with longer treatment. Outcomes by treatment duration could not be
analyzed as prolonged therapy was administered in
only seven of 95 studies.
Considering the difficulties of conducting a
human trial, animal models create more controlled
conditions for comparing the efficacy of different
antibiotics. Animal trials allow control over the
type, duration and severity of disease, any surgical
debridement provided, the etiologic agents, and the
duration of follow-up. When lacking adequate evidence on drug efficacy, antibiotics for osteomyelitis
must often be chosen on the basis of their safety
profile. Patient adherence to the treatment, which
is better with simplified regimens, must also be
considered.
Available evidence suggests that oral antibiotic
therapy can be as effective as parenteral treatments. The evidence is strongest for fluoroquinolones, because they were used in more recent, wellplanned comparative studies. Oral clindamycin has
also compared favorably with parenteral regimens
in one trial.24 These favorable results largely derive
from the excellent bioavailability and bone penetration of these classes of antibiotics. Oral treatments have the advantage of reduced duration of
hospitalization and health care costs. For organisms
resistant to oral drugs, outpatient parenteral antibiotic treatment (OPAT) has been successfully
employed.105 Newer methods of using parenteral
therapy are also available. Vancomycin has been
administered by continuous infusion and teicoplanin
has been administered three times weekly to treat
staphylococcal osteomyelitis.33,38 Indeed, the latter
approach appears more feasible and deserves consideration in those countries where teicoplanin is
available.
Cephalosporins were used in many of the osteomyelitis studies and were generally found to be
effective. Most of the studies used intravenous
cephalosporins, although oral agents, e.g., cephalexin, are often used clinically. Once-daily administered drugs, such as ceftriaxone, are preferred,
especially for outpatient therapy.105 As new oral
Antibiotic treatment of osteomyelitis
regimens become available, and the prevalence of
methicillin-resistant staphylococci increases, intravenous cephalosporins are likely to become a less
widely used treatment of osteomyelitis. New agents
with good oral bioavailability, high bone penetration,
and activity against MRSA (e.g., linezolid) have great
promise,106 but must be tested in clinical trials.107
The published reports on the antibiotic treatment
of osteomyelitis have not provided information
on most key treatment issues. All the antibiotic
classes listed in this review have demonstrated
efficacy in treating osteomyelitis, but well-designed
comparative studies to elucidate the most appropriate regimens are lacking. Therefore, the choice
of anti-biotic, unless limited by the sensitivity
of the etiologic organism(s), should be based
mostly on the safety of various agents for prolonged
use, and the cost and practicality of the chosen
regimen. Additional, properly designed, studies
are needed to ascertain the best agent(s), route,
and duration of antibiotic treatment for patients
with osteomyelitis.
135
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Acknowledgments
Thanks to Mark Shirtliff PhD and Jason H. Calhoun
MD for their helpful suggestions, to Kristi Overgaard,
BSc for manuscript editing and preparation, and the
personnel of the UTMB medical library for their help
in retrieving the published literature.
Conflict of interest: Benjamin Lipsky has received research sponsorship and has served as a
speaker for or a consultant to the following companies: Merck, Pfizer, Wyeth-Ayerst and Ortho-McNeil.
Luca Lazzarini has no competing interest to declare.
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