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A Review of Novel Antibiotic Regimens for the Treatment of Orthopedic Infections

Ioanna K. Bolia, MD; Sotirios Tsiodras, MD; George D. Chloros, MD; Angelos Kaspiris, BA; Thomas Sarlikiotis, MD; Olga D. Savvidou, MD; Panayiotis J. Papagelopoulos, MD, DSc, FACS


As a result of the increasing numbers of joint replacement surgeries and other implant-associated procedures performed, the incidences of periprosthetic joint infections and osteomyelitis are on the rise. Antibiotic resistance to gram-positive species, which are mostly isolated from such infections, is a significant obstacle in clinical practice. Promising clinical outcomes have been reported with the use of novel antibiotics for patients with periprosthetic joint infections and osteomyelitis. Further research is necessary for the establishment of these novel antibiotic therapies in routine clinical practice. [Orthopedics. 2018; 41(6):323–328.]


As a result of the increasing numbers of joint replacement surgeries and other implant-associated procedures performed, the incidences of periprosthetic joint infections and osteomyelitis are on the rise. Antibiotic resistance to gram-positive species, which are mostly isolated from such infections, is a significant obstacle in clinical practice. Promising clinical outcomes have been reported with the use of novel antibiotics for patients with periprosthetic joint infections and osteomyelitis. Further research is necessary for the establishment of these novel antibiotic therapies in routine clinical practice. [Orthopedics. 2018; 41(6):323–328.]

Tissue infection has become one of the major causes of hospitalization in the United States.1 Among the top 10 diagnoses resulting in a hospital stay, 3 are related to the field of orthopedics—osteoarthritis (5th); complications related to a device, an implant, or a graft (9th); and spine pathology (10th). Superficial or deep tissue infections are common in the field of orthopedics and can occur as primary disease or as postoperative complications.2 Periprosthetic joint infection (PJI) and osteomyelitis represent 2 types of musculoskeletal infections that are sometimes difficult to treat.3,4 Delay in diagnosis or inappropriate treatment strategy can result in severe patient disability or even death. The associated financial burden on the health care system is an additional problem that should not be overlooked.5 The prevalence of PJI has increased during the past 2 decades due to the dramatic increase in the number of total joint replacement surgeries performed.6 It has been reported that by 2030 the number of total knee arthroplasties and total hip arthroplasties performed in the United States will reach 3.48 million and 572,000, respectively.7

The main pathophysiologic mechanism behind PJI includes either direct contact or aerosolized inoculation of the implant and/or the surrounding tissues with microorganism(s) at the time of the procedure.8 Biofilm formation on the implant surface and subsequent microbial expansion has been the predominant theory behind the development of PJI.9 The clinical manifestation of PJI can vary and is usually affected by factors such as the patient's age and history of disease(s), surgical technique, type of prosthesis, and preventive measures against infections. Periprosthetic joint infection can become clinically apparent during the first year postoperatively. Early-onset PJI occurs less than 3 months postoperatively, whereas delayed-onset and late-onset PJI manifest between 3 and 12 months and 12 and 24 months postoperatively, respectively.10 Because there was significant variability in the definition of PJI, the Musculoskeletal Infection Society established specific criteria to aid clinicians in its diagnosis. One major criterion or 4 minor criteria should be met for the diagnosis of PJI to be made (Table 1).

Musculoskeletal Infection Society Criteria for the Diagnosis of Periprosthetic Joint Infection

Table 1:

Musculoskeletal Infection Society Criteria for the Diagnosis of Periprosthetic Joint Infection

Osteomyelitis is another severe orthopedic infection. The term osteomyelitis implies an infection that can be the result of hematogenous spread, contiguous infection, and infection that may be related to diseases that compromise the vascular supply and/or innervation of the bone.11 Hematogenous osteomyelitis primarily affects the metaphyses of long bones or the vertebral bodies. Implant-associated osteomyelitis can occur in cases of open fractures treated with the use of internal fixation devices such as intramedullary nails or plates and screws. Several diseases, including diabetes mellitus, cause impairment of the microcirculation and/or tissue innervation and increase the risk of osteomyelitis. The 2 widely acceptable classification systems for osteomyelitis are those described by Waldvogel et al12 and Cierny et al13 (Table 2). Acute osteomyelitis is characterized by severe tenderness, fever, and pain, which often cause the patient to restrict weight-bearing motion. Chronic osteomyelitis, which often follows a more indolent clinical course, is the result of bone infection in combination with the immunologic reaction of the host organism that is incapable of eradicating the disease.12,13

Cierny–Mader Classification System for Osteomyelitis

Table 2:

Cierny–Mader Classification System for Osteomyelitis

This article reports current therapeutic applications against PJI and osteomyelitis with a focus on novel antibiotics. The general principles of pathophysiology and the conventional therapeutic approach to these infections are discussed to improve understanding of the clinical benefits of these newer antimicrobial therapies.

Isolated Organisms and Current Treatment of PJI and Osteomyelitis

Gram-positive bacteria are the pathogens most frequently isolated in bone infections. Staphylococcus aureus (methicillin-susceptible Staphylococcus aureus, methicillin-resistant Staphylococcus aureus [MRSA], vancomycin-intermediate Staphylococcus aureus, vancomycin-resistant Staphylococcus aureus) is responsible for 80% to 90% of the cases of pyogenic osteomyelitis, whereas coagulase-negative staphylococci such as Staphylococcus epidermidis predominately infect orthopedic implants. Other commonly cultured microorganisms include gram-negative bacilli (Escherichia coli, Serratia species, Enterobacter species, Proteus species, Klebsiella species), streptococci, enterococci, and Pseudomonas aeruginosa. Mycobacterial and fungal osteomyelitis are generally uncommon, usually being seen in immunodeficiency and in patients with diabetes.14 The first cases of osteomyelitis due to Clostridium hydrogeniformans and pyogenic vertebral osteomyelitis due to Yersinia pseudotuberculosis were recently reported.15,16

The combination of a surgical procedure with systemic antibiotic administration is the gold standard approach to treating PJI. Various surgical strategies have been proposed, including tissue debridement with implant retention or removal of the prosthesis with 1- or 2-stage reimplantation, permanent prosthesis removal, amputation, and arthrodesis. Antibiotics alone have also been used to treat PJI. Acute osteomyelitis is usually treated with systemic antibiotics alone, whereas chronic osteomyelitis often requires the combination of surgery and antibiotics owing to the need to remove the necrotic tissue and/or reconstruct the bone to restore function.17 The choice of the appropriate antibiotic regimen should be guided by evidence-based protocols and the results of tissue culture. As a result of increasing antibiotic resistance, novel antibiotic therapies and innovative methods of administration have been developed to enhance the clinical effectiveness of antibiotics, reduce the incidence of side effects, and improve patient outcomes.18 Antibiotics that can be used for empiric or directed treatment of an implant-related infection are listed in Table 3.

Recommended Daily Dose of Intravenous Antibiotics Used as Monotherapy for Implant-Related Orthopedic Infections

Table 3:

Recommended Daily Dose of Intravenous Antibiotics Used as Monotherapy for Implant-Related Orthopedic Infections

Novel Antibiotics

Novel Oxazolidinone Antibiotics

Oxazolidinone antibiotics prevent the fusion of 30S and 50S ribosomal subunits in bacteria with subsequent inhibition of the protein synthesis. Linezolid was the first oxazolidinone used. These antibiotics are effective against gram-positive cocci, including methicillin-resistant staphylococci. In addition, oxazolidinones have high oral bioavailability in musculoskeletal tissues, making them useful against bone and implant-associated infections.19 A systematic review found an overall remission rate of 79.9% for 293 patients who were administered linezolid for acute or chronic orthopedic implant infection and followed at least 3 months. In the same study, anemia (13.4%) was the most commonly reported side effect of linezolid, followed by gastrointestinal symptoms (11.1%). Tedizolid and radezolid are newer oxazolidinones. In vitro studies have shown the potential of tedizolid to eliminate staphylococci isolated from PJI.20,21 Recently, a successful clinical outcome was reported for a patient who received tedizolid therapy for a PJI due to vancomycin-resistant Enterococcus.22 The activity of tedizolid against osteomyelitis due to methicillin-resistant Staphylococcus epidermidis was studied in a rat model.23 The authors reported the combination of tedizolid plus rifampin or vancomycin plus rifampin to be effective against osteomyelitis with retention of the foreign body compared with tedizolid alone or vancomycin alone. To the authors' knowledge, there are no reports regarding the clinical effectiveness of tedizolid for patients with implant-associated osteomyelitis. Radezolid is the newest antimicrobial in this category, and no clinical data have been reported. A clinical trial evaluating the safety and efficacy of radezolid for the treatment of pneumonia was recently completed.24

Novel Lipopeptides—Daptomycin

Daptomycin is particularly effective against gram-positive bacteria, and its bactericidal capability is concentration dependent.25 This cyclic lipopeptide acts by inserting its lipophilic tail into the bacterial cell membrane, causing membrane depolarization and efflux of potassium ions. This results in inhibition of the bacterial DNA, RNA, and protein synthesis leading to cell death. In the United States, this antibiotic has been approved for the treatment of complicated skin-related infections caused by staphylococci (including MRSA), streptococci, and vancomycin-susceptible enterococci.26 Malizos et al25 conducted a retrospective study of 6075 patients in Europe who received daptomycin for implant-associated infections, including both PJI and osteomyelitis. At 2-year follow-up, the success rates were 82.7% and 81.7% for Staphylococcus aureus and coagulase-negative staphylococcal infections, respectively. During the treatment period, the authors reported 78 (12.2%) adverse events, including rhabdomyolysis (0.5%), myositis (0.2%), myalgia (0.2%), increased serum creatine phosphokinase levels (1.7%), and patient death (1.6%). Forty-three (6.7%) of those side effects were daptomycin related.25

Novel Glycopeptide Antibiotics

With vancomycin being the prototype agent in this category, glycopeptide antibiotics inhibit the synthesis of peptidoglycan of the bacterial wall by binding to C-terminal D-alanine containing residues. This unique mechanism of action is responsible for the increased resistance of glycopeptide antibiotics compared with other antimicrobials. Vancomycin is the gold standard therapy for invasive MRSA infections. An increase in clinical failures had been observed with vancomycin, which has been associated with a rise in minimum inhibitory concentration.27 Oritavancin, a semisynthetic derivative of vancomycin, is a newer glycopeptide antibiotic that can be used as an alternative to vancomycin. Oritavancin is effective against resistant gram-positive infections, including MRSA and vancomycin-resistant Enterococcus.28 The long half-life of oritavancin allows it to be administered on a weekly basis. Two cases of prosthetic joint infection in which oritavancin was used in combination with single-stage revision/antibiotic spacer were recently reported. Both patients had satisfactory clinical outcomes that were believed to be the result of the prolonged half-life of this antibiotic.29 In addition, Delaportas et al30 reported the first case of Staphylococcus aureus osteomyelitis for which removal of a tibial nail was followed by 6 weeks of treatment with oritavancin with excellent clinical outcome. Telavancin has been reported to be effective against MRSA osteomyelitis as well as prosthetic joint infections when used for a prolonged period (up to 8 weeks). In a recent study, the infusion-related reactions were reported to be the most common complication of telavancin therapy.31 Dalbavancin is another second-generation glycopeptide that, similar to oritavancin, has a prolonged terminal half-life and can be administered once per week. Sufficient penetration and distribution of dalbavancin in bone and articular tissue has been reported, making this antibiotic preferable for the treatment of orthopedic infections, including PJI and osteomyelitis.32,33 The effectiveness of dalbavancin in the treatment of osteomyelitis was reported in vitro. Ramírez Hidalgo et al34 reported a case of a prosthetic knee infection due to oxacillin-resistant Staphylococcus epidermidis that was effectively treated with dalbavancin.35,36

Novel Cephalosporins

Ceftaroline and ceftobiprole are novel antibiotics that are effective against a broad spectrum of gram-positive organisms, including MRSA. These 2 antimicrobials can also be used as alternatives to vancomycin. In vitro experiments investigating the potential of ceftaroline to treat staphylococcal PJI (including MRSA and methicillin-resistant Staphylococcus epidermidis) have had promising outcomes.37–39 Malandain et al40 reported the outcomes of 16 patients who were treated for complex PJI using ceftaroline. Most patients had previous surgeries and a history of PJI. In 86% of the cases, ceftaroline was used in combination with another antimicrobial, mostly rifampin. The success rate was 44% at 6-month follow-up. Two patients experienced neutropenia after 2 weeks and after 8 weeks of treatment, respectively. The authors suggested closed hematologic monitoring in patients who receive ceftaroline for more than 2 weeks.40 One case of osteomyelitis involving the second and third metatarsophalangeal joints for which ceftobiprole was used as therapy was reported. This patient received intravenous ceftobiprole for 6 weeks in combination with local surgery to address concomitant septic arthritis and osteomyelitis caused by a polymicrobial infection that included MRSA and had a successful result.41 No impairment of complete blood count or renal function was observed in this patient.

Combination Therapies

Limited data exist regarding the outcomes of bone infections treated with a combination of newer antibiotics. Kurtzhalts et al42 reported the case of a 64-year-old man who was successfully treated for pubic symphysis osteomyelitis using ceftolozane and tazobactam. This novel antibiotic regimen was combined with surgical debridement to eradicate multidrug-resistant Pseudomonas, which was the identified cause of osteomyelitis following bladder fistula formation after radiation in this patient.42 A combination of linezolid plus rifampicin as an adjunct to surgery resulted in successful treatment of recurrent MRSA osteomyelitis in a 79-year-old woman.43 The combination of antibiotics, careful drug monitoring, and surgical treatment was helpful in avoiding the thrombocytopenic effect of linezolid and preserving its bacteriostatic properties against the MRSA. Dupieux et al44 reported that oxacillin can enhance the otherwise weak intracellular activity of daptomycin in an acidic environment. Oxacillin significantly improves the effectiveness of daptomycin against the osteoblastic reservoir of Staphylococcus aureus. An in vitro study showed that ceftazidime in combination with avibactam could potentially be useful against KPC-producing Klebsiella pneumoniae clinical isolates.45 Rico-Nieto et al46 reported the case of a patient who had a multidrug-resistant Klebsiella pneumoniae infection on lumbar arthrodesis implants. This patient was successfully treated with ceftazidime plus avibactam without removal of the implants. When different antibiotics were compared with combination therapies against PJI in a mouse model, the combination of rifampin with ceftaroline or linezolid was superior to daptomycin, ceftaroline, or doxycycline monotherapy.47Table 4 provides a summary of recent studies reporting the dose and type of combined antibiotic therapy used to successfully treat orthopedic infections.

Summary of the Case Studies Reporting the Treatment of Orthopedic Infections Using a Combination of Novel Antibiotics With or Without Surgical Debridement

Table 4:

Summary of the Case Studies Reporting the Treatment of Orthopedic Infections Using a Combination of Novel Antibiotics With or Without Surgical Debridement


Periprosthetic joint infection and osteomyelitis are mostly caused by staphylococcal species and are often difficult to treat. As a result of increased antibiotic resistance and failure rates with the use of traditional antibiotics, new antimicrobials are urgently needed. Tedizolid, radezolid, dalbavancin, oritavancin, and ceftobiprole represent this new generation of antimicrobials that are now being implemented in clinical practice and have shown promising clinical outcomes. The combination of novel antibiotics with conventional therapies, including surgery, might be useful for preventing the side effects of these new medications until more safety data become available.


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Musculoskeletal Infection Society Criteria for the Diagnosis of Periprosthetic Joint Infection

Major CriteriaMinor Criteria
A sinus tract is communicating with the prosthesis A pathogen is isolated by culture from at least 2 separate tissue or fluid samples obtained from the affected prosthetic jointElevated serum erythrocyte sedimentation rate and serum C-reactive protein concentration Elevated synovial leukocyte count Elevated synovial neutrophil percentage Presence of purulence in the affected joint Isolation of a microorganism in 1 culture of periprosthetic tissue or fluid Greater than 5 neutrophils per high-powered field in 5 high-powered fields observed from histologic analysis of periprosthetic tissue at 400× magnification

Cierny–Mader Classification System for Osteomyelitis

Anatomical type
  IMedullary osteomyelitis
  IISuperficial osteomyelitis
  IIILocalized osteomyelitis
  IVDiffuse osteomyelitis
Physiological class
  AGood immune system and delivery
  BCompromised locally or systemically; requires suppressive or no treatment; minimal disability
  CTreatment worse than disease; not a surgical candidate
Factors affecting physiological class
  SystemicMalnutrition, renal or hepatic failure, diabetes mellitus, chronic hypoxia, immune disease, extremes of age, immunosuppression, immune deficiency, tobacco abuse, alcohol abuse, malignancy
  LocalChronic lymphedema, venous stasis, major vessel compromise, arteritis, extensive scarring, radiation fibrosis, small-vessel disease, neuropathy

Recommended Daily Dose of Intravenous Antibiotics Used as Monotherapy for Implant-Related Orthopedic Infections

AntibioticRecommended Daily Dose
Pencillin G24/25 million units intramuscularly in 5 to 6 doses
Amoxicillin8 g in 4 doses
Clavulanate0.8 g in 4 doses
Flucloxacillin8 g in 4 doses
Cefazolin8 g in 4 doses
Cefuroxime6 g in 4 doses
Ceftriaxone2 g in 1 dose
Ceftazidime6 g in 3 doses
Cefepime6 g in 3 doses
Imipenemencilastatin2 to 4 g in 4 doses
Meropenem6 g in 3 doses
Vancomycin30 mg/kg in 2 doses

Summary of the Case Studies Reporting the Treatment of Orthopedic Infections Using a Combination of Novel Antibiotics With or Without Surgical Debridement

Study (Year)Type of InfectionAntibiotic Therapya
Kurtzhalts et al42 (2017)Pseudomonas aeruginosa pubic symphysis osteomyelitisVancomycin plus ceftolozane/tazobactam for 6 weeks Vancomycin dose was adjusted to achieve levels between 15 and 20 µg/mL. Ceftolozane/tazobactam was dosed at 1.5 g intravenously every 8 hours.
Ashizawa et al43 (2016)Recurrent methicillin-resistant Staphylococcus aureus implant-related osteomyelitisLinezolid dose to 600 mg/h at 12-hour intervals and performed combination therapy with rifampicin
Rico-Nieto et al46 (2018)Infection of lumbar arthrodesis implants by Klebsiella pneumoniae producing carbapenemase D, OXA-48 subgroupCeftazidime/avibactam
Laurent et al48 (2015)Nocardia knee prosthetic joint infectionMeropenem/doxycycline followed by ceftriaxone/doxycycline
Håkanson et al49 (2014)Vancomycin-resistant Staphylococcus epidermidis prosthetic joint infectionLinezolid and rifampin

The authors are from the First Department of Orthopedic Surgery (IKB, GDC, TS, ODS, PJP) and the Fourth Department of Internal Medicine (ST), National and Kapodistrian University of Athens, Medical School, Attikon University Hospital, Athens, and the Laboratory of Molecular Pharmacology (AK), School of Health Sciences, University of Patras, Patras, Greece.

Dr Papagelopoulos is a previous Blue Ribbon Article Award recipient (Orthopedics, May/June 2018).

Drs Bolia and Tsiodras contributed equally to this work and should be considered as equal first authors.

The authors have no relevant financial relationships to disclose.

Correspondence should be addressed to: Panayiotis J. Papagelopoulos, MD, DSc, FACS, First Department of Orthopedic Surgery, National and Kapodistrian University of Athens, Medical School, Attikon University Hospital, Rimini 1, Chaidari, 12462, Athens, Greece ( pjporthopedic@gmail.com).


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