Pharmacokinetics and Pharmacodynamics of Antibiotics in Bone

Abstract

Chronic osteomyelitis requires prolonged antibiotic treatment, has a high recurrence rate, and can cause irreversible damage. Also, the number of orthopedic device-related infections continues to increase [1]. Therefore, adequate antibiotic treatment and surgical prophylaxis are critical. Therapeutic success is primarily determined by the antimicrobial activity against the infecting pathogen and the rate and extent of antibiotic penetration into bone. Adequate bone penetration has to be ensured as antibiotics need to reach effective concentrations at the infection site to kill bacterial pathogens. Therefore studying the time course and extent of bone penetration before launching a clinical effectiveness trial is important. The aim of this chapter is to review the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics in bone and present methods that support optimized evidence-based selection of antibiotic dosage regimens.

Physiologically Based Population Pharmacokinetic Modeling Approach for Ciprofloxacin in Bone of Patients Undergoing Orthopedic Surgery

“…Blood vessels in bone are located in Haversian and Volkmann’s canals that transverse the matrix. Bone cells represent only 1–2% of total bone mass and in their most mature form as osteocytes are trapped inside the matrix. , The inorganic matrix accounts for ∼65% of total bone mass and consists of calcium phosphate crystals (hydroxyapatite) deposited inside the organic bone matrix. Currently no bioanalytical methods are available to reliably quantify drug concentrations separately within those different components of bone.…”

“…Osteomyelitis typically requires prolonged antibiotic treatment, has a high risk of recurrence and may irreversibly damage the bone. − Successful surgical prophylaxis and postsurgical antibiotic therapy are critical for the respective prevention and treatment of osteomyelitis. , Both require the attainment of effective concentrations at the infection site in bone . Thus, studying the extent and time-course of antibiotic bone penetration is important, especially as bone is less vascularized than many other regions , for example, the lungs or skin . Such studies are challenging to perform and analyze, and several limitations apply to the vast majority of bone penetration studies…”

“…The need for sufficient samples over a sufficient time can be addressed by an informative study design in which bone and plasma samples are collected from a number of different patients with the times of sample collection being distributed across a sufficient time after a single dose or across a dosing interval in a multiple dosing regimen. Such a sparse sampling protocol for each of the included patients together with population PK analysis makes possible a description of the whole time-course of concentrations in both bone and plasma . Subsequent Monte Carlo simulations can predict the expected probability of PK/PD target attainment for clinically relevant dosage regimens, as we have reported using traditional compartmental modeling in which the physiological context is not considered. , …”

“…9 Thus, studying the extent and time-course of antibiotic bone penetration is important, especially as bone is less vascularized than many other regions , for example, the lungs or skin. 10 Such studies are challenging to perform and analyze, and several limitations apply to the vast majority of bone penetration studies. 11 While microdialysis studies conducted over several hours can be very informative in understanding penetration of drugs in many soft tissues, this technique has substantial limitations when applied to bone.…”

Salmonella Osteomyelitis in a Healthy Child: Case Report and Review of Literature

“…Another advantage of quinolones is that they generally penetrate well into cells. 20,21 In conclusion, we decided to use oral ciprofloxacin because we wanted to assure a good bone penetration guaranteeing microbiological cure, taking into consideration the adverse effects reported, which we had none during treatment, and according to what is reported in the literature, we can make an early switch to oral antibiotics to be completed at home with complete remission, reducing hospital stay and associated comorbidities.…”