LAPORAN PENELITIAN

The Antibiotic Use in Osteomyelitis Infection

Oleh :

dr. Daniel Ronadi

(NIM : 188070101011001)

Pembimbing :

Dr. dr. Panji Sananta, M. Ked, SpOT(K).

PROGRAM STUDI ILMU BEDAH

PROGRAM PENDIDIKAN DOKTER SPESIALIS I
FAKULTAS KEDOKTERAN UNIVERSITAS BRAWIJAYA
RUMAH SAKIT SAIFUL ANWAR
 MALANG
2021

THE ANTIBIOTIC USE IN OSTEOMYELITIS

INFECTION

Introduction: Osteomyelitis is a serious infection of the bone. One of the therapi of

osteomyelitis is antibiotics treatment. Antibiotics treatment has evolved substansially, but bone
infection are still a challenge. Antimicrobial therapy also complicated with antibiotic resistant
organism. Therefore, a systematic review is needed to assess the antibiotic use in osteomyelitis
infection.
Method: Articles were searched by using Pubmed with keywords "antibiotics", "osteomyelitis"
and its combination. The authors used 5 years publication date and English language to select an
appropriate journal.
Result: The author identified 14 relevant articles with antibiotics use in osteomyelitis. All of the
cases were about chronic osteomyelitis and osteomyelitis in diabetic foot ulcer. Osteomyelitis in
other site of long bones need longer duration treatment than long bone osteomyelitis. In acute
osteomyelitis in children, antibiotics treatment can switch from IV to oral antibiotics. And
chronic osteomyelitis need longer treatment to resolve than acute osteomyelitis.
Conclusion: Antibiotics still mainstay treatment with surgery for osteomyelitis treatment. With
acute, children, and long bone only need shorter treatment than chronic, adult and non long bone
osteomyelitis.
Keywords: Antibiotics, Osteomyelitis
Introduction

Osteomyelitis is a serious infection of the bone that can be either acute or chronic

(Momodu, 2021). The annual incidence of osteomyelitis was 21,8 cases per 100.000 person-

years. Rates increased, from 11,4 cases per 100.000 person-years from 1969 to 1979 to 24,4 per

100.000 person-years in the period from 2000 to 2009 (Kremers, 2015). There is still a limited

data about osteomyelitis incidence in Indonesia. But there is data from orthopaedic department in

Hasan Sadikin Hospital in Bandung, the incidence of chronic osteomyelitis in Indonesia is 0,5 to

2,4 / 100.000 populations. And from a study, they found 151 cases of chronic osteomyelitis in

Hasan Sadikin Hospital from 2011 to 2016 (Indira, 2017)

Antibiotics is one of the therapy for osteomyelitis. Antibiotics treatment of osteomyelitis

has evolved substantially over the past 80 years. Numerous antimicrobial agents with distinct

spectrums of action, pharmacokinetics, and pharmacodynamics have been used in its treatment.

Surgical techniques, including muscle grafts, the Ilizarov technique, and antibiotic bone cements,

have been applied. However, bone infections are still a challenge (Jorge, 2010). New studies are

challenging the dogma (for example, the antimicrobial must be given parenterally) (Cortes-

Penfield, 2019). Antimicrobial therapy is now also complicated by the increasing prevalence of

antibiotic resistant organism, especially methicillin-resistant Staphylococcus aureus (Rao, 2011).

Therefore, a systematic review is needed to assess the antibiotics use in osteomyelitis

infection.
Methods

The following strategy was used terms on PubMed search engine were “antibiotics”,

“osteomyelitis” and its combination. Preferred Reporting Items for Systematic Reviews and

Meta-Analyses (PRISMA) guidelines were used to perform the comprehensive data collection. A

bibliometric evaluation was done on all the search results. After searching with those keywords,

the authors used 5 years publication date and English language to select the appropriate journal

and documents. Journals and documents were reviewed from title and abstract and followed

inclusion and exclusion criteria. The inclusion criteria were an original article, with type are

clinical trial, meta-analysis, or randomized controlled trial and discuss about antibiotics use in

osteomyelitis. The exclusion criteria were a case reports, review articles and no full-text paper.

Journal search strategy showed in figure 1.

 Article identification through
database searching Article before than 2016
(n=266) (n=225)

Article screened Article without full text data

(n=39) (n=2)

Article excluded
Fulltext article assessed
(n=23)
(n=37)
- Research with
German Language
(n=2)
- Research didn’t
focus on
antibiotics in
osteomyelitis
Studies included to analysis (n=9)
(n=14) - Journals already
more than 5 years
Figure 1. Flow diagram of search strategy (n=3)
- Research still in
progress (n=5)
- Documents from
book (n=5)
Result

The initial PubMed search yielded 266 titles with 39 full-text articles and documents

assessed according to the inclusion and exclusion criteria. There were 25 articles and documents

eliminated according to the exclusion criteria. The final total number of articles which analysis

was 14 articles and documents.

Table 1. Studies included to analysis

Author Σ Sample Design Case
Menetrey et al., 2018 17 Prospective Osteomyelitis, hip surgery
Alcobendas et al., 2018 253 Prospective Osteomyelitis and septic arthritis
Chen et al., 2017 1526 Prospective Osteomyelitis, diabetic foot ulcer
Mangwani et al., 2016 100 Prospective Toe osteomyelitis
Huang et al., 2019 3598 Review Osteomyelitis
Lavery et al., 2020 155 Prospective Osteomyelitis, diabetic foot ulcer
Lemaignen et al., 2017 394 Retrospective Vertebral osteomyelitis
Luo et al., 2016 51 Retrospective Chronic osteomyelitis
Mortazavi et al., 2018 183 Review Chronic osteomyelitis
Van Vugt et al., 2018 413 Review Chronic osteomyelitis
Wunsch et al., 2019 101 Retrospective Tibial Osteomyelitis
Sun et al., 2018 72 Retrospective Chronic osteomyelitis
Hanley et al., 2021
Graaf et al., 2017 313 Prospective Acute Osteomyelitis in children

Based on table 1, most of the cases from this journal are chronic osteomyelitis and

diabetic foot ulcers. 4 studies used the retrospective cohort method, 6 studies used the

prospective method, and 4 studies were a review. The total number of patients was 5419 samples

with the largest number of samples in a study by Huang et al., 2019 which had a total of 3598

patients with lower extremity osteomyelitis.

 Table 2. Summary Antibiotics Use in Osteomyelitis

Author Case Antibiotics Use

Menetrey et al., 2018 Osteomyelitis, hip surgery Duration is 4 to 6, with chronic
is 8 to 12 weeks
Alcobendas et al., 2018 Oral antibiotics save and
Osteomyelitis and septic arthritis effective in children case
Chen et al., 2017 Osteomyelitis in diabetic foot
related to drug resistant
Osteomyelitis, diabetic foot ulcer infection
Mangwani et al., 2016 Prophylactic antibiotic does
not reduce incidence
Toe osteomyelitis osteomyelitis in toe
Huang et al., 2019 Short course antibiotics (< 4
weeks) as effective as long
Osteomyelitis course
Lavery et al., 2020 Duration of antibiotics for
osteomyelitis did not change
Osteomyelitis, diabetic foot ulcer even use NPWT as treatment
Lemaignen et al., 2017 Vertebral osteomyelitis Majority case in acute
vertebral osteomyelitis
received antibiotics in 90 days
Luo et al., 2016 Chronic osteomyelitis Combination therapy (with
loaded calcium sulfate) have
better results than monotherapy
Mortazavi et al., 2018 Cranial osteomyelitis Broad spectrum antibiotics 8-
20 weeeks
Van Vugt et al., 2018 Use of antibiotic-loaded
sponges in the treatment of
Chronic osteomyelitis osteomyelitis is limited
Wunsch et al., 2019 Dalvabancin as alternative
Tibial Osteomyelitis antibiotics for osteomyelitis
Sun et al., 2018 Implanted antibiotics can
improve results for chronic
Chronic osteomyelitis osteomyelitis
Hanley et al., 2021 One of standard treatment for
chronic and refracter
osteomyelitis is culture
Chronic osteomyelitis directed antibiotic
Graaf et al., 2017 IV switch to oral antibiotic < 7
weeks have better outcome
Acute Osteomyelitis in children than > 7 days
 Based on the table above, all of study agree antibiotics in one of the treatment for

osteomyelitis beside the surgery. 4 studies use chronic osteomyelitis case for their study. From

the site of osteomyelitis, most of studies use of lower extremity osteomyelitis case. 1 article

discuss about cranial osteomyelitis and 1 article discuss about vertebral osteomyelitis. And from

age perception, 2 journal focus on osteomyelitis in children, while the other journal discuss

osteomyelitis in general, children and adult.

Table 3. Summary of Microorganism and Choice of Antibiotics

Author Microorganism Choice of antibiotics

Menetrey et al., 2018
Alcobendas et al., 2018
Chen et al., 2017
Mangwani et al., 2016
Huang et al., 2019
Lavery et al., 2020
Lemaignen et al., 2017
Luo et al., 2016
Mortazavi et al., 2018
Van Vugt et al., 2018
Wunsch et al., 2019
Sun et al., 2018
Hanley et al., 2021
Graaf et al., 2017
Staphylococcus aureus
Staphylococcus aureus, Staphylococcus
pneumoniae, Kingella kigae
Multidrug resistant or methicillin resistant
Staphylococcus aureus
No specific microorganism
No specific microorganism
No specific microorganism
Staphylococcus aureus, Enterobacteriae,
Streptococcal
S aureus, MRSA, P. aeruginosa
S aureus, streptococci, anaerob
microorganism
S aureus, E colli
S. aureus, MRSA, enterococci,
streptococci, Propionibacterium acne
S. aureus, Klebsiella, E. colli, S.
pneumoniae
S. aureus, Streptococcus
S aureus, Kingella kigae, Streptococcus
Afabicin
Cephalosporin, amoxicillin-
clavulanate, clindamycin
No specific antibiotics
Fluocloxacillin
No specific antibiotics
No specific antibiotics
Anti-staphylococcal beta
lactam / Fluoroquinolone +
rifampicin, 3rd gen
cephalosporin and/or
fluoroquinolone, amoxicillin
Levofloxacin, Cefazolin,
Ceftazidime, Vancomycin +
calcium sulfate(local)
Carbapenem + ciprofloxacin
Gentamycin-sulfate/
gentamycin-crobefate implant
Dalvabancin
Broad spectrum antibiotics +
Gentamycin (for impregnated
bead)
Culture directed antibiotics,
cephalosporins and
aminoglycosides
Flucloxacillin and ceftriaxone
 Based on the table above, all of study said Staphylococcus aureus is the most etiology of

osteomyelitis, in many site. Other microorganism who also found in many studies is

Streptococcus, even not as many as Staphylococcus. 3 studies don’t mention the specific

organism as the etiology of osteomyelitis.

For the choice of antibiotics, cephalosporine and quinolone become first choice in 10

studies, while the other studies use other antibiotics or did not mentioned the choice.

Discussion

This systematic review shows that the antibiotics is one of the treatment for osteomyelitis

beside the surgery. In many case, even in children or adult, in acute or chronic condition, and in

many location, like extremity, spinal, and cranial, antibiotics still have crucial part of therapy for

the patient, but have some different approach.

Observational study by Lemaignen et al.,(2017) showed that antibiotics therapy in

vertebral osteomyelitis need a long time in antibiotics use. The median duration of antibiotics

treatment was 90 days, with only 27,1% cases received less than 45 days of antibiotics treatment

(Lemaignen et al., 2017) . The other study, comprehensive review from Mortazavi, the result was

appropriate broad-spectrum antibiotics therapy over the period of 8 – 20 weeks is one of

essential therapy to managing cranial osteomyelitis. But culture-directed antimicrobial therapy

for a minimum of 3 months remains the general protocol because treatment of cranial

osteomyelitis may take up for several months for complete resolution (Mortazavi et al.; 2017). In

other study, diabetic foot become one of main factor how long the antibiotics need to be given.

From journal by Huang et al, the patients with diabetic foot and osteomyelitis need > 3 months of
antibiotics for non surgically treated patients. This journal also said, patients with vertebral

osteomyelitis are treated with 6 weeks antibiotics, but the chronic osteomyelitis of the long bones

need 4-6 weeks course of parenteral antibiotics, followed oral therapy from weeks to months

(Huang et al, 2019).

The results of antibiotics treatment in chronic osteomyelitis also have different results

between children and adult. Hanley et al, in their journal said Surgical debridement and culture-

directed antibiotics are the mainstays of treatment. And if after the appropriate therapy for 4 to 6

weeks already done but the osteomyelitis still cannot be resolved, the diagnosis of chronic

refractory osteomyelitis (CRO) becomes appropriate (Hanley et al; 2021). So the conclusion is,

the standart duration of antibiotics treatment for osteomyelitis is 4 – 6 weeks. But there was

another journal which research duration in children case. Alcobendas et al make comparison

between the treatment adjusted by age. The results was Staphylococcus aureus was more

prevalent in older children, while Kingela kingae was more frequent in younger children. Even in

75% of cases still need surgical treatment because the protocol or diagnostic purpose, Kingela

kingae infection involve a less severe process, allowing quick oral therapy, with this research

suggested IV antibiotics for 2 to 4 days, followed by oral antibiotics 2 – 3 weeks (Alcobendas et

al,; 2018). Journal from Graaf also said the suggested duration for parenteral antibiotic treatment

ranges from 3 days up to 6 weeks, resulting from several, mainly observational, but this

recommendation have relatively poor level of evidence. But from recent retrospective cohort

study of 1969 children in the USA found that early switch to oral therapy (median 4 days) was as

effective as prolonged i.v. treatment (Graaf et al; 2017).

Antibiotics treatment duration in chronic osteomyelitis is longer than antibiotics

treatment in acute osteomyelitis. One of the journal said acute osteomyelitis will respon the
therapy for 4 – 6 weeks, and if do not respond the diagnosis of chronic refractory osteomyelitis

(CRO) becomes appropriate (Hanley et al; 2021. Sun et al, 2018). In chronic osteomyelitis,

multitherapy antibiotics can give better results than monotherapy, and oral antibiotics was not

administer in most journal.

From the etiology, almost every journal said S. aureus is the most common etiology of

osteomyelitis, in any site. Only 3 studies don’t mention the microorganism. S. aureus is part of

normal flora, but in some situation,S. aureus become a virulent, with well armed, pathogen

(Archer, 1998). With extensive virulence factor and increasing in the resistance of virulence

pathogen, make “new face” of S. aureus like MRSA. This condition give bad impact to decrease

of S. aureus infection. Other etiology is Streptococcus. Streptococcus is a flora normal too.

Streptococcus is common pathogens beyond the neonatal period through the age of 4. But, now

become rare because the vaccination, and replaced by Kingella kigae (DeRonde, et al. 2018).

Antibiotics choice also become a topics until right now. In osteomyelitis case, the

antibiotics need to have good penetration into bone and joint tissue to eradicate the

microorganism. There was literature who study more than 30 antibiotics, and the results almost

all of antibiotics have good penetration in bone and joint. Of note, studies on joint space

penetration was fewer than studies on bone tissue penetration. But flucloxacillin had poor

profiles in terms of joint space penetration (Thabit et al. 2019). All studies still believe

antibiotics is a mainstay treatment for osteomyelitis. And culture directed antibiotics for specific

etiology. Most of the studies choose beta lactam and fluoroquinolone for antibiotics treatment.

Beta-lactam agents are the drugs of choice for treating AHO due to K kingae, GAS (Group A

Streptococcus), or Streptococcus pneumoniae (Thakolkaran, 2019).

Conclusion

Antibiotics still mainstay treatment with surgery for osteomyelitis treatment. With acute,

children, and long bone only need shorter treatment than chronic, adult and non long bone

osteomyelitis. The most of etiology in any site is Staphylococcus aureus, and cephalosporin as

beta lactam antibiotics and fluoroquinolone still be the first choice in culture directed antibiotics

treatment for osteomyelitis.

Reference

Momodu I.I, Savaliya V. (2021). Osteomyelitis. StatsPearls Publishing.

Kremers, H. M., Njowo M. E., Ransom J.E., Wood-Wentz C. M., Melton L. J., Huddleston P.
M., (2015). Trends in Epidemiology of Osteomyelitis. J Bone Joint Surg Am., 97(10): 837–
845.
Indira, S.A., Lokarjana, L., Pohan, D.K. (2017). Gambaran Pasien Osteomyelitis Kronis di
Bagian Bedah Ortopedi RSUP dr. Hasan Sadikin Bandung. Repository Unjani.
Cortes-Penfield, N.W., Kulkarni P.A. (2019). The Hystory of Antibiotic Treatment of
Osteomyelitis. Open Forum Infect Dis., 6(5): ofz 181.
Rao, N., Ziran B.H., Lipsky, B.A. (2011). Treating Osteomyelitis: Antibiotics and Surgery. Plast
Reconstr Surg. Jan;127 Suppl 1: 177S-187S.
Jorge, L.S., Chuerie, A.G., Rossit, A.R.B. (2010). Osteomyelitis: a current challenge. Braz J
Infect Dis. May-Jun;14(3):310-5
Archer G. L. (1998). Staphylococcus aureus: a well-armed pathogen. Clin Infect Dis. May;26(5):
1179-81
DeRonde K. J., Girotto J. E., Nicolau D. P. (2018). Management of Pediatric Acute
Hematogenous Osteomyelitis, Part I : Antimicrobial Stewardship Approach and Review of
Therapies for Methicillin-Susceptible Staphylococcus aureus, Streptococcus pyogenes, and
Kingella kigae. Pharmacotherapy. Sep;38(9):947-966.
Thakolkaran N, Shetty A. K., (2019). Acute Hematogenous Osteomyelitis in Children. Oschsner
J. Summer;19(2):116-122
Alcobendas R., Remesal A., Murias S., Nunez E., Calvo C. (2018). Outpatients with acute
osteoarticular infections had favourable outcomes when they received just oral antibiotics
without intravenous antibiotics. Acta Paediatrc. Oct;107(10):1792-1797
Menetrey A, Janin A, Pullman J, Overcash J S., Haouala A, et al. (2019). Bone and Joint Tissue
Penetration of the Staphylococcus-Selective Antibiotic Afabicin in Patients Undergoing
Elective Hip Replacement Surgery. Antimicrob Agent Chemother. Feb 26;63(3)
Mangwani J, Gulati A, Benson R, Cichero M, Williamson D. (2015). Role of prophylactic
antibiotics in lesser toe fusion surgery: A prospective randomised controlled trial. Foot and
Ankle Surgery.
Huang C, Hsieh R, Yen H, Hsu T, Chen C, et al. (2019). Short- versus long-course antibiotics in
osteomyelitis: A systematic review and meta-analysis. International Journal of
Antimicrobial Agents 53;246-260
Lavery L A., Davis K E., Fontaine J L, Farrar J D., Bhavan K, et al. (2020). Does negative
pressure wound therapy with irrigation improve clinical outcomes? A randomized clinical
trial in patients with diabetic foot infections. The American Journal of Surgery. 220;1076-
1082
Van Vugt TAG, Walvaren JMB, Geurts JAP, Arts JJC. (2018). Antibiotic-Loaded Collagen
Sponges in Clinical Treatment of Chronic Osteomyelitis. The Journal of Bone & Joint
Surgery. Dec 19;2153-2161
Wunsch S, Krause R, Valentin T, Prattes J, Janata O, et al. (2019). Multicenter clinical
experience of real life Dalbavancin use in gram-positive infections. International Journal
of Infectious Disease. 81;210-214
Luo S, Jiang T, Yang Y, Yang X, Zhao J. (2016). Combination therapy with vancomycinloaded
calcium sulfate and vancomycin loaded PMMA in the treatment of chronic osteomyelitis.
BMC Musculoskeletal Disorder. 17:502
Graaf H, Sukhtantar P, Arch B, Ahmad N, Less A, et al. (2017). Duration of intravenous
antibiotic therapy for children with acute osteomyelitis or septic arthritis: a feasibility
study. Health Technology Assesment. 21(48);1366-5278
Sun P, Ma Y, Zhang Y, Cheng M. (2018). Application of antibiotic impregnated beads on the
patients with tibial chronic osteomyelitis. Pak J Pharm Sci. Nov 31(6);2783-2786
Mortazavi M M., Khan M A, Quadri S A., Suriya S S., Fahimdanesh K M., et al. (2017). Cranial
Osteomyelitis: A Comprehensive Review of Modern Therapies. World Neurosurg.
Mar;111:142-153.
Lemaignen A, Ghout I, Dinh A, Gras G, Fantin B, et al. Characteristics of and risk factors for
severe neurological deficit in patients with pyogenic vertebral osteomyelitis: A case-
control study. Medicine (Baltimore). May;96(21)
Chen Y, Ding H, Wu H, Chen H. (2017). The Relationship Between Osteomyelitis Complication
and Drug-Resistant Infection Risk in Diabetic Foot Ulcer: A Meta-analysis. The
International Journal of Lower Extremity Wound
Hanley M. E., Hendriksen S., Cooper J. S. (2020). Hyperbaric Treatment Of Chronic Refractory
Osteomyelitis. StatsPearls Publishing.