2 Antibiotics for Orthopaedic Infections

Alaina S. Ritter and Sandra B. Nelson

Antibiotics play a critical role in the treatment of bone and joint infections. In clinical practice, antibiotics may be delivered intravenously, orally, or topically, alone or as part of a delivery mechanism. This chapter will discuss the most commonly used oral and intravenous antibiotics in orthopaedic infections, their efficacy and bioavailability, and important considerations when using these antibiotics for patient care. This chapter will additionally focus on the use of topical antibiotics and nondegradable/biodegradable carriers for antibiotic delivery, such as the use of heat-stable antibiotics in cement spacers. The information presented here is designed for use as a clinical reference to provide guidance on the care of patients with orthopaedic infections including osteomyelitis, septic joints, and periprosthetic joint infections.

Intravenous antibiotics – oral antibiotics – topical antibiotics – heat stable antibiotics – bone and joint infections – orthopaedic infections – musculoskeletal infections – periprosthetic joint infections – antibiotic carriers – cement spacers

2 Antibiotics for Orthopaedic Infections

Practical Tips

Antibiotics may be administered intravenously, orally, topically, and/or in combination with a carrier.
Factors such as known or suspected organisms, bioavailability, and bone penetration may all impact antibiotic selection.
Unique host factors such as medication allergies, drug interactions, immunocompromise, and liver/kidney function may also affect choice of antibiotic.
A multidisciplinary approach may be beneficial for the treatment of orthopaedic infections.

2.1 Systemic Antibiotics

2.1.1 Definitions

Surgical antimicrobial prophylaxis refers to the use of antimicrobial therapy prior to surgery to prevent surgical site infection (SSI).

Preemptive therapy is when antibiotic therapy is used after microorganisms have been introduced into a wound to prevent overt infection. For example, in patients with an open fracture awaiting internal fixation, a short course of antibiotics is recommended to prevent infection.

Empiric therapy is when an antibiotic is used due to the presence of infection but prior to the identification of the causative microorganisms. In this situation, clinicians must consider the type of infection and most likely resistance pattern when designing a treatment regimen. Antibiotics should be adjusted as soon as additional culture information is available.

Targeted therapy is when antibiotic treatment is tailored to the microorganism and its antibiotic susceptibility. Targeted therapy also involves determining the duration of therapy and need for intravenous (IV) versus oral therapy depending on the type of infection.

Suppressive therapy is the use of long-term oral antibiotics to prevent symptoms of infection in patients in whom cure is not possible.

2.1.2 Antibiotic Selection and Administration

The optimal antimicrobials for surgical prophylaxis should target the most common organisms that can cause SSI, rapidly achieve bactericidal tissue levels, and have an excellent safety profile (▶ Table 2.1). ¹ Cephalosporins such as cefazolin are first-line prophylaxis for orthopaedic procedures. Vancomycin should be used (in addition to, or in lieu of cefazolin) if there is a history of methicillin-resistant Staphylococcus aureus (MRSA). Because cefazolin is a more effective prophylactic than vancomycin against sensitive organisms and offers the addition of some gram-negative coverage, some centers recommend the use of both agents when MRSA is present, although there may be a higher nephrotoxicity risk with combination therapy, and the optimal approach in this setting is not yet clear. Either vancomycin or clindamycin can be used if there is a life-threatening penicillin and/or cephalosporin allergy. ² Gentamicin may be added for additional gram-negative coverage, such as when there is an open fracture. ¹ Penicillin may be added to prevent clostridial infection when there is fecal or soil contamination.

**Table 2.1** Surgical prophylaxis
Clinical scenario	Antimicrobial and dose	Notes
Standard prophylaxis	Cefazolin 2 g	3 g if >120 kg; administer within 30–60 minutes of the incision; redose every 4 hours for normal renal function
Personal history of MRSA (infection or colonization)	Vancomycin 15 mg/kg (maximum dose 2 g)	Administer vancomycin starting within 2 hours of incision, optimally to be completed 1 hour prior to incision; consider addition of cefazolin to vancomycin
Serious β-lactam allergy	Vancomycin 15 mg/kg (maximum dose 2 g) or clindamycin 900 mg	Administer vancomycin starting within 2 hours of incision, optimally to be completed 1 hour prior to incision; clindamycin redosing interval: 6 hours
Desired gram-negative coverage (e.g., open fracture; environmental contamination)	Addition of gentamicin 5 mg/kg to above	Dose based on adjusted body weight if BMI >30
Soil (e.g., farm injury) or fecal contamination (Clostridia)	Addition of penicillin G 4 million units to above	Redose every 4 hours for normal renal function
Abbreviations: BMI, body mass index; MRSA, methicillin-resistant Staphylococcus aureus.

Antibiotic administration should be timed so that the antibiotic serum and tissue concentration is bactericidal at the time when the incision is made. ³ The optimal time for preoperative antibiotic administration is within 60 minutes prior to the time of incision. ¹ Vancomycin requires a longer administration time (over 1 to 2 hours prior to surgical incision) and this time should be taken into account when vancomycin is utilized. ¹ In patients undergoing aseptic joint arthroplasty, only one perioperative antibiotic dose is necessary. There is no increased risk of subsequent surgical site or prosthetic joint infection (PJI) when a single dose is administered, as compared with multiple doses. This also applies even if allografts are used. ² ^, ³ There is also no role for prolonged surgical antimicrobial prophylaxis due to the presence of drains. ³

The selection of antimicrobials for empiric and targeted therapy requires consideration of multiple factors. The clinician should first consider the most likely pathogens causing the bone and joint infection, such as Staphylococci, Streptococci, and Enterobacteriaceae. Institutional and local antibiotic resistance patterns and changes in patterns over time should be reviewed to guide antibiotic therapy, along with prior available culture data for the specific patient. Risk factors for multidrug resistant infections should be identified, including prior history or known colonization with MRSA, residence in countries where drug resistance is more common, and patients with multiple comorbidities or a history of extensive antibiotic exposure. Patients who use intravenous drugs may be at higher risk of MRSA, Pseudomonas aeruginosa, and Candida infections. Other host factors that impact antimicrobial therapy selection include medication allergies and intolerances, renal and hepatic function that might affect antibiotic dosing, and impaired immune function, such as due to organ transplantation, chemotherapy, corticosteroid, or other immunosuppressive therapies.

The penetration of antibiotics into bone and devitalized tissue is important to consider when designing a regimen. Because of inflammation, bone penetration of antibiotics may be higher in viable infected bone with intact perfusion than in uninfected bone. Nonetheless, certain antibiotics may still require adjusted dosing strategies to ensure appropriate bone penetration. Antibiotic penetration into bony sequestrum and necrotic bone is minimal given limited to nonexistent vascular flow. Additionally, peripheral vascular disease also limits bone penetration, particularly to the lower extremities. Bone penetration of specific antibiotics is discussed in greater detail next (Intravenous versus Oral Antibiotics). Of note, bone penetration data does not always correlate directly with efficacy of treatment. This discrepancy results from experimental differences in antibiotic dosing, initial bone health, and timing of bone harvesting compared with the typical clinical situation.

Biofilm formation can reduce antibiotic efficacy. A biofilm is comprised of sessile microbes contained within an extracellular matrix. This extracellular membrane protects the bacteria from antibiotics, the host immune response, and environmental stressors. The readiness with which organisms attach to surfaces and form biofilms depends on a variety of factors, including the species of bacteria, the roughness and porosity of the attachment surface, and the hydrophobicity/hydrophilicity of the environment. Once established, the permeability of the biofilm is limited. Neutrophils and macrophages have limited entry and have reduced efficacy in eliminating sessile bacteria. For most antibiotics, penetration into the biofilm is also limited. The minimal inhibitory concentration (MIC) of antibiotics to treat specific free-living bacteria may not be relevant when applied to the same bacteria within biofilms. The minimum biofilm eradication concentration (MBEC) measures in vitro antibiotic susceptibility of microbes in biofilms. However, clinically validated parameters are not yet available.

2.1.3 Intravenous versus Oral Antibiotics

The use of IV versus oral antibiotics to treat orthopaedic infections is another area of debate. A 2013 Cochrane review of patients with chronic osteomyelitis showed no difference between oral and IV antibiotics. ⁴ It was noted, however, that many studies contained bias and were performed at a time when antibiotic resistance was less problematic. The recently published OVIVA (Oral versus intravenous antibiotic treatment for bone and joint infections) trial, which included 1,050 patients from 30 hospitals in England and Scotland, showed that oral antibiotic therapy was noninferior to IV antibiotic therapy for the treatment of bone and joint infections. ⁵ This was a parallel group, randomized, unblinded, and noninferiority trial. The primary outcome was treatment failure within 1 year of randomization. Data is otherwise limited on this topic, and practice patterns vary. A hybrid approach, with a transition to oral therapy after an initial IV course, has been used satisfactorily in some cases.

Intravenous Antibiotics

▶ Table 2.2 summarizes commonly used IV antibiotics in bone and joint infections and their bony penetration. Beta-lactam antibiotics include penicillins, cephalosporins, and carbapenems. Bone levels for most beta-lactams are only 5 to 20% of serum levels, but this is still adequate for bone levels to exceed the MIC in most cases when administered intravenously. Vancomycin is often used as a first-line treatment for MRSA and other methicillin-resistant infections, as well as in the setting of serious beta-lactam allergy. However, vancomycin is slow to reach optimal concentrations in bone, especially cortical bone. Daptomycin can be used for treating MRSA and other methicillin-resistant infections. In in vivo models, daptomycin has activity in osteomyelitis and can penetrate into biofilms, synovial fluid, and cancellous bone, ⁶ ^, ⁷ although clinical data evaluating these properties are more limited.

**Table 2.2** Intravenous antibiotics for treatment including bone penetration: gram-positive infections
Drug (dose)	Typical dosing frequency (average weight/renal function)	Spectrum	Ratio of bone/serum levels, %	Comments
Agents for primarily gram-positive infections
Oxacillin (2 g) Nafcillin (2 g)	Every 4 hours	Methicillin-susceptible staphylococci	10	Confirm susceptibility prior to treatment
Ampicillin (2 g)	Every 4–6 hours for ampicillin alone, every 6–8 hours in combination with sulbactam	Streptococci, Cutibacterium species, most Enterococcus spp.	17	Often used for targeted therapy and infections due to Enterococcus species
Ampicillin-Sulbactam (1.5–3 g)	Every 6–8 hours	Streptococci, methicillin-susceptible staphylococci; also active against some gram-negatives and anaerobes	12–17	Often used for empiric therapy
Cefazolin (1–2 g)	Every 8 hours	Methicillin-susceptible staphylococci, most streptococci; active against some gram-negatives	7.5–37	Tolerated better than oxacillin for methicillin-susceptible staphylococcal infections
Vancomycin (1 g)	Every 8–24 hours based on trough levels	Gram-positive bacteria, staphylococci, streptococci, Cutibacterium spp., Enterococcus spp.	5–21	Often used for empiric therapy and definitive therapy for resistant gram-positive infections
Daptomycin (6–8 mg/kg)	Every 24 hours	Gram-positive bacteria, staphylococci, streptococci, and Enterococcus spp.	7	Doses may need to be adjusted based on the MIC of the organism
Agents for primarily gram-negative infections
Ceftriaxone (1–2 g)	Every 24 hours	Respiratory and GI gram-negatives, including Haemophilus influenzae, susceptible Enterobacteriaceae; also active against many gram-positives including streptococci	5–19	Frequently used for targeted outpatient IV therapy
Ceftazidime (1–2 g)	Every 8 hours, dosing based on severity	Susceptible respiratory gram-negatives, Enterobacteriaceae, Pseudomonas aeruginosa	3–27
Cefepime (1–2 g)	Every 8 hours	Similar to ceftazidime but with higher in vitro activity against oxacillin-susceptible staphylococci, streptococci, and resistant Enterobacter species	87–100	Confirm MIC of Enterobacter species prior to treatment; monitor for neurotoxicity especially if renal function impaired
Imipenem (500 mg to 1 g)	Every 6 hours	Similar to cefepime plus resistant gram-negative bacteria including Enterobacter spp. and Pseudomonas aeruginosa	16–48	Treatment of possible or proven multidrug-resistant gram-negative bacteria
Meropenem (500 mg)	Every 8 hours	Similar to cefepime plus resistant gram-negative bacteria including Enterobacter spp. and Pseudomonas	17	Treatment of possible or proven multidrug-resistant gram-negative bacteria
Piperacillin (2–4 g)	Every 4–6 hours	Generally used in combination with tazobactam: Streptococci, staphylococci (penicillin susceptible), Enterobacter spp., and Pseudomonas aeruginosa	5–7.5
Piperacillin (3 g)/tazobactam (0.375 g)	Every 6 hours		20/25
Abbreviations: GI, gastrointestinal; IV, intravenous; MIC, minimal inhibitory concentration. Source: Adapted with permission from Spellberg and Lipsky ⁸ and incorporating data from Zimmerli W and Sendi P. Systemic antibiotics. In: Kates SL, Borens O, eds. Principles of Orthopedic Infection Management. Thieme; 2017: 70. ²⁰