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Osteomyelitis: an overview of antimicrobial therapy
Diana Gomes1, Margarida Pereira2, Ana Francisca Bettencourt1,*
Research Institute for Medicines and Pharmaceutical Sciences (iMed
...
It can affect all ages, involve any bone, become a chronic disease and cause persistent morbidity
...
Bacteria in biofilm persist in a low metabolic phase, causing persistent infection
due to increased resistance to antibiotics
...
Osteomyelitis
treatment implies the administration of high doses of antibiotics (AB) by means of endovenous and oral
routes and should take a period of at least 6 weeks
...
These
systems allow the local delivery of AB in situ with bactericidal concentrations for long periods of time
and without the toxicity associated with other means of administration
...

The study methodology consisted of a literature review in Google Scholar, Science Direct, Pubmed,
Springer link, B-on
...

Uniterms: Osteomyelitis/pharmacological treatment
...
Staphylococcus
aureus/presence/Osteomyelitis
...

A osteomielite é um processo inflamatório do tecido ósseo, de origem infecciosa, que resulta em destruição
inflamatória, necrose e formação de novo osso
...
Apesar dos progressos na quimioterapia
infecciosa, o tratamento da osteomielite é caro e difícil, em particular quando associada à presença
de biofilmes bacterianos, especialmente de Staphylococcus aureus e Staphylococcus epidermidis
...
Os sistemas de veiculação localizada de
fármacos, utilizando materiais não biodegradáveis (polimetilmetacrilato) ou biodegradáveis e osteoativos
como os cimentos ósseos de ortofosfatos de cálcio e vidro bioativo, surgiram como uma alternativa
promissora para o tratamento da osteomielite
...
O presente trabalho propõe uma revisão da literatura relativa às causas, à patogenia e ao
tratamento farmacológico da osteomielite
...
Foram
revistos e analisados diversos artigos publicados desde o ano de 1979
...
Osteomielite/terapia antimicrobial
...
Antibióticos/uso/tratamento da osteomielite
...
F
...
Faculdade de Farmácia, Universidade de Lisboa
...
Prof
...
E-mail:
asimao@ff
...
pt

Review

Brazilian Journal of
Pharmaceutical Sciences
vol
...
1, jan
...
, 2013

14

D
...
Pereira, A
...
Bettencourt

INTRODUCTION

TERMINOLOGY

Osteomyelitis known since antiquity was first
described by Chassaignac in 1852 (Lew, Waldvogel,
1997; Lindfors et al
...
The word “osteomyelitis”
is derived from the ancient Greek words osteon (meaning
bone) and muelinos (meaning marrow) and simply means
an infection of the medullar portion of the bone
...

Osteomyelitis is a disease in transition, with
ongoing changes in predisposing factors, causative
organisms and treatment (Tice et al
...
It affects
both adults and children
...
e
...

Prognosis of osteomyelitis is largely dependent on
the mechanism of infection, the virulence of the infecting
organism and the immune status and comorbid conditions
of the patient (Tice et al
...

The mortality rate is low, unless associated with sepsis or
when a serious underlying medical condition is present
...

Osteomyelitis is a disease which is heterogeneous
in its pathophysiology, clinical presentation and management
...

It continues to be a frequent indication for the use of
intravenous antibiotic therapy as well as a major healthcare
cost item (Tice et al
...
Carrier systems that deliver
antibiotics locally are widely-used experimentally and
clinically to treat osteomyelitis because they can provide
higher concentrations of drugs at the infected site (Zhang
et al
...

Osteomyelitis remains a severe problem worldwide,
causing plenty of hospital admissions and entailing considerable expense (Frank et al
...
This review focuses on
current knowledge of the disease and the progress being
made in antimicrobial treatment including the use of local
drug delivery systems
...

The term is often used interchangeably with hematogenous
osteomyelitis and refers to osteomyelitis before osteonecrosis has occurred (Lew, Waldvogel, 2004; Chihara,
Segreti, 2010)
...

Untreated or due to treatment failure, the infection
can progress to a more chronic phase
...
It is associated with formation of a large area of
devascularized dead bone, a sequestrum (Lew, Waldvogel,
2004; Chihara, Segreti, 2010; Lindfors et al
...


PATHOGENIC MECHANISM OF INFECTION
Experimental animal models of bone infection have
revealed that bone is highly resistant to infection
...

The pathophysiology of osteomyelitis is multifactorial and begins with spread of the organism
...
, 2009)
...

Based upon the pathogenic mechanisms of infection,
various types of osteomyelitis can be grouped according
to the source of the infection (Lew, Waldvogel, 2004):
1) Osteomyelitis secondary to a contiguous focus of
infection (e
...
, 2009);
3) Osteomyelitis following hematogenous spread of
infection, which is the major mechanism in vertebral osteomyelitis and in children (Macnicol, Watts,
2005; Labbé et al
...

Whatever the source of infection, once an organism
reaches the bone it causes acute inflammation
...
, 2009; Montanaro et al
...


15

Osteomyelitis: an overview of antimicrobial therapy

Certain major causes of infection, such as Staphylococcus aureus, adhere to bone by expressing receptors
(adhesins) for components of bone matrix (fibronectin,
laminin, collagen, and bone sialoglycoprotein); the expression of the collagen-binding adhesion permits the
attachment of the pathogen to cartilage (Lew, Waldvogel,
1997; Brady et al
...

During acute infection, phagocytes attempt to contain invading microorganisms and, in the process, generate
toxic oxygen radicals and release proteolytic enzymes that
may lyse the surrounding tissues (Lew, Waldvogel, 1997)
...
With the progression to a chronic
state, the ischemic necrosis of bone results in the separation
of devascularized fragments, which are called sequestrum
(Lew, Waldvogel, 1997; Mcphee, Papadakis, 2007)
...
, 2006; Montanaro et al
...
, 2012)
...


CAUSAL ORGANISMS
The most common pathogens responsible for osteomyelitis in humans are Staphylococcus species, followed
by Enterobacteriaceae and Pseudomonas species (Gogia
et al
...
A summary of different etiology related to
age and the predisposing conditions is shown in Table I
...
I - A large inoculum of bacteria reaches the medular channel; II - (Acute state) Pus

resulting from inflammatory response spreads into vascular channels; III - (Chronic state) Vascular channels are compressed and
obliterated by the inflammatory process, and the resulting ischaemia also contributes to bone necrosis
...
, 2010; Zimmerli, 2010; Eid,
Berbari 2012)
Age
Newborn babies
Children
Adults
Susceptibility factors
Injectable drug users
Imunocompromised
Urinary infection
Spinal column surgery
Orthopedic fixation devices
Hospitalization (nosocomial source)
Diabetes mellitus, vascular
insufficiency, contaminated open
fracture

Etiology
S
...
, Streptococcus (group A and B)
S
...
, Streptococcus (group B), Haemophilus influenzae
S
...
aureus, P
...

S
...
, Mycobacterium avium complex, Candida
albicans
P
...

S
...
aureus, coagulase-negative staphylococci, Propionibacterium spp
...
aeruginosa, Candida spp
...
aureus, Staphylococci coagulase negative, Streptococcus spp
...
, Gram-negative bacilli, anaerobes

16

in all age groups (Jorge et al
...

There has been an increase in methicillin-resistant S
...
Coagulase-negative staphylococci are
often seen in association with foreign bodies, such as
prosthetic joints (Chihara, Segreti, 2010)
...

Anaerobic bacteria as Bacteroides spp
...
, Propionibacterium acnes
and Clostridium spp
...
, 2010; Furustrand et al
...

Anaerobes may contribute to polymicrobial osteomyelitis
in vasculopathic infection such as diabetic foot infection
(Eid, Berbari, 2012)
...
, 2012)
...
For example in immunocompromised patients, pathogens such as Bartonella henselae, Aspergillus
spp
...
, 2004; Chihara, Segreti, 2010;
Eid, Berbari, 2012)
...
, 2008)
...

The difference in pathophysiology of various types
of osteomyelitis mandates specific therapeutic strategies
aimed at the eradication of the infection while preserving
bone integrity and function (Eid, Berbari, 2012; Moenster

D
...
Pereira, A
...
Bettencourt

et al
...
Early antibiotic treatment, before extensive
destruction of bone or necrosis, produces the best results
and must be administered by the intravenous route for at
least four (and usually six) weeks to achieve an acceptable
rate of cure (Lew, Waldvogel, 1997)
...
Antibiotics considered bactericidal against the infecting organisms are often considered
necessary (Darley, MacGowan, 2004)
...

The treatment of chronic osteomyelitis is more
complicated and requires a multidisciplinary approach
in 3 phases: surgical debridement, systemic antibiotic
therapy for 4 to 6 weeks and local antibiotic delivery
systems (Sánchez et al
...
The goal of surgical treatment is to
convert an infection with dead bone to a situation with
well-vascularized tissues that are readily penetrated by
antibiotics, making prolonged drug treatment unnecessary
(Mader et al
...

Osteomyelitis surgical treatment is beyond the scope
of the present review
...
, 2010; Malizos et al
...

Next, we will discuss the classes of antibiotics used
in oral and systemic antibiotic treatment and the use of local antibiotic delivery systems mainly in the management
of chronic osteomyelitis
...
An early switch to oral
administration is appropriate for antibiotics with good
bioavailability and bone penetration (Lew, Waldvogel,
2004; Eid, Berbari, 2012)
...
The
advantages and disadvantages of oral and parenteral routes
are summarized in Table II
...
e
...
As new oral regimens become available, and the
prevalence of MRSA increases, intravenous beta-lactams
are likely to become less widely used for osteomyelitis

17

Osteomyelitis: an overview of antimicrobial therapy

TABLE II - Advantages and disadvantages of parenteral, oral and local antibiotic therapy (adapted from Gitelis, Brebach, 2002;

Ambrose et al
...
, 2005)
Therapy
Type
Parenteral

Oral

Local

Advantages

Disadvantages

- Delivery of antibiotic to areas that cannot be reached
with oral therapy
- Choice of a large set of agents
- Arrest or eradication of infection in most cases (in
conjunction with surgical debridement)

- Often requires hospitalization
- Lack of patient compliance
- Systemic drug toxicity
- Even with prolonged intravenous antibiotic therapy
relapse of bone infection is not uncommon
- Expensive
- Ease of administration
- Therapeutically unpredictable
- Reduced duration of hospitalization and health care costs - Capacity for replace the prolonged courses of
parenteral therapy is controversial
- Limited choice of agents
- Avoid high serum concentrations of the antibiotic
- Lack of proven efficacy in good randomized clinical
- Deliver antibiotic directly to the infection site
trials
- Reduced duration of hospitalization and health care costs

treatment (Eid, Berbari, 2012)
...

Oral cephalosporins, e
...
, cephalexin, ceftriaxone are often
used clinically
...
, 2005)
...

Fluoroquinolones
The fluoroquinolones have gained popularity in
recent years because of their excellent oral bioavailability
and bone penetration (Lew, Waldvogel, 2004)
...

Extensive in vitro studies have demonstrated the role of
the second generation fluoroquinolones like ciprofloxacin,
ofloxacin, and pefloxacin against some Gram-positive
organisms (Pawar, Bhandari, 2011)
...
, Enterococcus spp
...

The third-generation quinolone, levofloxacin, has
improved Streptococcus spp
...
The newer
fourth-generation fluoroquinolones, gatifloxacin, moxifloxacin, and gemifloxacin cover many gram-positive and
gram-negative organisms, and certain anaerobes
...
aeruginosa as ciprofloxacin (Calhoun, Manring, 2005)
...
aeruginosa, Serratia spp
...
aureus has yet to be shown in controlled studies
(Lew, Waldvogel, 2004)
...
aureus strains (Pawar, Bhandari, 2011), therefore the use
of a second agent in the treatment of S
...
Fluoroquinolones
have also been reported to inhibit fracture healing, but
the clinical significance of this observation is not known
(Aslam, Darouiche, 2009)
...
Several studies have shown that oral
treatment with rifampicin in combination with various
antibiotics as ciprofloxacin, ofloxacin, or fusidic acid is
effective in bone staphylococcal infections in the presence
of implants or prosthetic joints (Lew, Waldvogel, 2004;
Pawar, Bhandari, 2011)
...

High serum concentrations, bactericidal levels in
infected and sclerotic bone, good intracellular concentrations, and good activity against S
...
Like rifampicin, early development of resistance, is one of the prime limitations of fusidic
acid, unless used in combination (Pawar, Bhandari, 2011)
...

Glicopeptides
The only drugs with a constant efficacy against all
the staphylococcal strains, and which have been extensively studied in the treatment of bone infections, are
glycopeptides, in particular vancomycin (Yin et al
...
Vancomycin is used to treat MRSA and
ampicillin-resistant Enterococcus species (Eid, Berbari,
2012)
...
Increased prevalence of vancomycin-resistant S
...
,
2009; Pawar, Bhandari, 2011; Vilhena, Bettencourt, 2012)
...
(2012) states that despite adequate dosing,
30% to 50% of patients experience infection recurrence
within 12 months
...
,
2005; Aslam, Darouiche, 2009; Pawar, Bhandari, 2011)
...

Linezolid, which can be administered either orally
or intravenously, represents a new class of antibiotic with
no cross-resistance to other antibiotics
...
faecium
and E
...
It has been proved effective for
treating serious infections, including osteomyelitis (Calhoun, Manring, 2005)
...
Additionally, no large randomized trials
have been published on the use of linezolid for orthopaedic
infections (Pawar, Bhandari, 2011)
...
, 2007; Pawar, Bhan-

D
...
Pereira, A
...
Bettencourt

dari, 2011; Vilhena, Bettencourt, 2012)
...
However, no randomized and controlled trials comparing the
effectiveness and safety of daptomycin with other antibiotics used to treat bone and joint infections have been
completed (Lamp et al
...

In addition, case reports suggest the potential for
quinupristin-dalfopristin the first parenteral streptogramin and tigecycline, a novel parenteral glycylcycline
to cure chronic osteomyelitis, but clinical data are limited
(Fraimow, 2009; Kaya et al
...
Long-term safety and efficacy data needs to be
produced with regard to the use of these promising newer
agents for treating osteomyelitis due to MRSA and vancomycin-resistant Enterococcus (VRE)
...

Local Antibiotic Therapy

Even with prolonged intravenous antibiotics, there
is a significant relapse rate in the treatment of chronic
osteomyelitis
...
, 2001; Gitelis, Brebach, 2002; Nair et al
...

The in situ implantation of a local antibiotic delivery
system works to obliterate bacteria in the area as well as
to reduce the dead space in the bone (Nair et al
...

Its use results in a lower serum antibiotic concentration
than that associated with systemic administration, thereby
reducing toxicity-related side-effects (Joosten et al
...
, 2012) (Table II)
...
However, a combination therapy of antibiotics is useful to reduce the toxicity of individual agents,
to prevent the emergence of resistance and to treat mixed
infections involved in osteomyelitis (Nandi et al
...

The local delivery of antibiotics in the treatment of
osteomyelitis has been used for decades regardless of the
controversy over its effectiveness (Gitelis, Brebach, 2002)
...
Generally,

19

Osteomyelitis: an overview of antimicrobial therapy

TABLE III - Antimicrobial therapy of osteomyelitis in adults for selected organisms (Chihara, Segreti, 2010; Sia, Berbari, 2010;

Carvalho et al
...
5 µg/mL

Penicillin-G, 20 MU IV
24 h for 4-6 wks or
ceftriaxone, 1-2 g IV or IM
24 h for 4-6 wks
Penicillin-G, 3-4 MU (IV) q
4 h for 4-6 wks or
ampicillin, 2 g IV q 4 h; the addition of
gentamicin, 1
mg/kg IV/IM q 8 h for 1-2 wks optional

Alternative choice
Ceftriaxone, 1-2 g IV q 24 hrs or
clindamycin, 900 mg IV q 8 h
Linezolid, 600 mg (PO/IV) q 12 h for
6 wks (or linezolid plus rifampicin* PO
600-900 mg/day) or daptomycin,
6 mg/kg IV daily for 6 wks
Vancomycin*, 15 mg/kg IV q 12 h for
4-6 wks

Vancomycin*, 15 mg/kg IV q 12 h for
4-6 wks; the addition of gentamicin,
1 mg/kg IV/IM q 8 h for 1-2 wks optional

Ciprofloxacin, 500-750 mg PO q 12 h for
4-6 wks
Cefepime, 2 g IV q 12 h for 4-6 wks or
Ciprofloxacin, 750 mg PO q 12 h for 4-6
Pseudomonas aeruginosa or
meropenem, 1 g IV q 8 h for 4-6 wks
wks, or ceftazidime, 2 g IV q 8 h
Enterobacter spp
...
5-3 g
Carbapenem antibiotic or a combination of
Mixed infections possibly involving
IV q 6 h or piperacillin/tazobactam,
fluoroquinolone plus clindamycin, 900 mg
anaerobic bacteria
3
...
i
...
i
...
5-1 mg/kg daily for 2-3 wks followed by fluconazole, 6 mg/kg PO/IV
Candida species
daily for 6-12 mo
Legend: h-hour; IM-intramuscular; IV-intravenous; q- every; mo-months; MU-million units; PO-per os; t
...
d- three times a day;
wks-weeks
...
In
Table IV the main advantages and disadvantages of these
two types of systems are outlined
...
, 2006;
Azi et al
...

Gentamicin-impregnated beads were created by
Klemm (1979) and were used to occupy dead space after
debridement of infected bone related to chronic osteomyelitis
...
4% was achieved (Azi et al
...


PMMA beads containing gentamicin have been approved for use in treatment of osteomyelitis in Europe, in
the 1970s under the trade name of Septopal®
...
It
is still not accepted by the Food and Drug Administration
(FDA) in the USA (Walenkamp, 2009)
...
Physician-made
beads are individually manufactured by the surgeon using
commercially available PMMA polymer mixed with a
powdered antibiotic or can be created with the assistance
of an individually made bead mold (Holtom, Patzakis,
2003) (Figure 2)
...


20

D
...
Pereira, A
...
Bettencourt

TABLE IV - Advantages and disadvantages of different type of antibiotic carrier systems (adapted from Gursel et al
...
, 2002; Gogia et al
...
, 2010)

Biodegradable

Non-biodegradable

Carrier type

Advantages
- Represent the current gold standard for local
antibiotic delivery
- Proven to be successful with several antibiotics
- Easy procedure for insertion in the body

Disadvantages
- Low biocompatibility, cytotoxic effects
- Second surgery may be needed to remove the cement
beads (which is costly and painful)
- Polymerization process could cause thermal damage and
neutralize the antibiotic
- Poor antibiotic elution properties
- Slow residual release of antibiotics for undefined periods;
risk of resistance
- Do not form a firm bond with bone
- Initial burst of antibiotics to the infection site
- No large human trials have been published
- None of these materials has been approved for antibiotic
delivery in osteomyelitis treatment by the FDA

- Material properties can be adjusted to vary the
release rate of the antibiotic
- Osteoconductivity and osteoinductivity
- One-stage surgery
- Wider selection of antibiotics including
thermolabile ones

FIGURE 2 - The in situ implantation of antibiotic-impregnated beads, as a local antibiotic delivery system, works to obliterate

bacteria in the area as well as to reduce the dead space in the bone
...
Placement of these beads is a simple
procedure and often performed at time of initial debridement of chronic osteomyelitis (Gogia et al
...
Local
antibiotic treatment is also substantially less expensive
than systemic therapy, which can cost hundreds of dollars
per day in an outpatient setting and much more in the hospital setting
...
Another argument against
its use is the lack of proof of efficacy in good randomized

clinical trials (Walenkamp, 2009)
...
(2011)
...

Many antibiotics have been shown to maintain efficacy when mixed with PMMA bone cement
...
, 2009; Azi et al
...
Tobramycin and vancomycin, both water soluble

21

Osteomyelitis: an overview of antimicrobial therapy

and available in powder form, have also been included in
PMMA (Gogia et al
...
But the resistance to these
routinely used antibiotics has led to an intensive search
for alternative, more effective antibiotics to be loaded
into PMMA bone cement
...
(2001) described
the treatment with amphotericin B-loaded bone cement
of a case of osteomyelitis due to Candida albicans in
an adult who had undergone multiple revisions of a hip
prosthesis
...
(2008) evaluated the
efficacy of grepafloxacin loaded acrylic bone cement
(polymethylmethacrylate, PMMA) for the treatment of
experimentally chronic osteomyelitis induced in rabbits
...
(2012) evaluated the bioactivity
of meropenem loaded bone cement with possible application in Gram negative bone infections
...
, 2010)
...
, 2001;
Efstathopoulos et al
...
, 2012), it is
expected they will remain in the near future an effective drug delivery system for local antibiotic therapy in
osteomyelitis
...

Major advantages of these implants include obliteration of
dead space, aid to bone repair, wider selection of antibiotics including thermolabile ones and no need for a second
surgery for removal (Table IV) (Gitelis, Brebach, 2002)
...
Interesting reviews on the subject can
be found in Kanellakopoulou, Giamarellos-Bourboulis
(2000) and Nandi et al
...

Impregnation of antimicrobial agents within osteoconductive bioceramics (calcium sulphate, tricalcium
phosphate or hydroxyapatite) has been proposed for the
local management of osteomyelitis and to aid dead space
management mainly for the delivery of aminoglicosides
such as tobramycin (Nelson et al
...
, 2005; Xie et al
...


Besides bioceramics, other bioactive inorganic materials are being explored as silicate (Mäkinen et al
...
, 2010) and borate-based bioglasses (Xie et
al
...

These bone-filling materials have the advantage of
converting to a hydroxyapatite (HA)-type material, the
main mineral constituent of bone, and bond strongly with
bone and soft tissue in vivo, promoting osteogenesis on
their surfaces (Mäkinen et al
...
, 2010)
...
, 1994; Kanellakopoulou, Giamarellos-Bourboulis, 2000; Ambrose et al
...
, 1995) especially for antibiotics
such as ampicillin, tobramycin and gentamicin
...
, 2008)
...
In this sense, several
biocomposites composed of biodegradable polymers such
as chitosan poly(lactic-co-glycolic acid), poly(D,Llactide) or poly-ε-caprolactone and inorganic materials
like tricalcium phosphate, hydroxyapatite and bioactive
glasses have been tried (Mäkinen et al
...
, 2008; Miyai et al
...
, 2010), showing promising results for curing chronic osteomyelitis in
animal models (Table V)
...


CONCLUSIONS
Osteomyelitis is a serious deep bone infection with
significant morbidity and high rates of recurrence
...
aureus) can arise from a variety of
etiologies such as trauma, nosocomial infections or after
implant replacement surgery
...

Currently, the standard treatment of osteomyelitis
includes debridement of infected tissues, dead space
management, and 4 to 6 weeks of parenteral antibiotics
...
Gomes, M
...
F
...
aureus

Rabbits

Joosten et al
...
, 2009

Calcium sulphate

Tobramycin sulphate S
...
, 2002

Hydroxyapatite

Vancomycin

Rabbits

Shirtliff et al
...
aureus

Rats

Korkusuz et al
...
, 2005

Gentamicin

S
...
, 1995

PEG, PLGA

Tobramycin,
Cefazolin

S
...
, 2004

Polyhydroxy-alkanoate

Sulbactam,
cefoperazone,
ampicillin

S
...
, 2001

Polylactide/polyglicolide

Gentamicin

S
...
, 1994

P(SA-RA)

Gentamicin

S
...
, 2008

P(SA-RA)

Gentamicin

S
...
, 2007

Borate

Vancomycin

MRSA

Rabbits

Xie et al
...
, 2009

Boro-silicate

Ceftriaxone–
sulbactam

S
...
, 2011

Chitosan, borate glass

Teicoplanin

S
...
, 2010

PLGA, bioactive glass

Ciprofloxacin

S
...
epidermidis, E
...
aeruginosa

Rabbits

Mäkinen et al
...
aureus

Rabbits

Alvarez et al
...
o
...
milleri, B
...
, 2008

S
...
o
...
aureus; PEG-poly(ethylene glycol); PLGA-poly(DL-lactic-co-glycolic
acid); P(SA-RA)-Poly(sebacic-co-ricinoleic-ester-anhydride)
...
However poor vancomycin bone penetration
and increasing rates of heteroresistance and glycopeptide
tolerance have encouraged the search for newer agents,
namely linezolid, daptomycin, quinupristin-dalfopristin
and tigecycline
...
The most commonly used non-biodegradable
carrier material has long been PMMA in the form of
beads or bone cement
...
This is an emerging
area of research with great potential in the near future to
treat osteomyelitis
...
Nuno Diogo, Head of Orthopaedic Department of Hospital Curry Cabral (Lisbon) for
his motivation concerning the writing of the article
...


DECLARATION OF INTEREST
The authors report no conflicts of interest
...


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...
; MOUJIR, L
...
;
DELGADO, A
...
; EVORA, C
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Received for publication on 01st August 2012
Accepted for publication on 09th January 2013



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