Penetration of amoxycillin/clavulanate into human bone

Weismeier, K.; Adam, Dieter; Heilmann, Hans-Dietrich; Koeppe, P.

doi:10.1093/jac/24.suppl_b.93

Cited by 22 publications

(11 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The concentrations in cortical and cancellous bone were correlated for both drugs (r ϭ 0.75). This agrees with the data from Weismeier et al (54) and indicates that the equilibration rates between cortical bone and serum and between cancellous bone and serum were probably similar. This was confirmed by population PK modeling.…”

Section: Vol 53 2009 Amoxicillin-clavulanic Acid Population Pk-pd 2573supporting

confidence: 92%

“…The amoxicillin and clavulanic acid concentrations in bone that have been published previously vary widely (1,3,24,50,54). Average bone concentration/serum concentration ratios differ up to 3-fold for amoxicillin and 25-fold for clavulanic acid between various studies.…”

Section: Discussionmentioning

confidence: 99%

“…For the timing of perioperative prophylaxis and surgery, it seems critical to know how fast efficacious concentrations are achieved and how long they are maintained. Modeling of the time course of bone concentrations for penicillins is important, since the shape of the concentration-time curve affects the time above the MIC.The concentrations of amoxicillin and clavulanic acid in bone were studied in the 1980s (1,3,24,54), and only the bone concentration/serum concentration ratios were reported. As these bone concentration/serum concentration ratios change over time, they are a suboptimal measure of the extent of tissue penetration (36, 47).…”

mentioning

confidence: 99%

“…The concentrations of amoxicillin and clavulanic acid in bone were studied in the 1980s (1,3,24,54), and only the bone concentration/serum concentration ratios were reported. As these bone concentration/serum concentration ratios change over time, they are a suboptimal measure of the extent of tissue penetration (36,47).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Bone Penetration of Amoxicillin and Clavulanic Acid Evaluated by Population Pharmacokinetics and Monte Carlo Simulation

Landersdorfer

Kinzig

Bulitta

et al. 2009

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Amoxicillin (amoxicilline)-clavulanic acid has promising activity against pathogens that cause bone infections. We present the first evaluation of the bone penetration of a beta-lactam by population pharmacokinetics and pharmacodynamic profiling via Monte Carlo simulations. Twenty uninfected patients undergoing total hip replacement received a single intravenous infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid before surgery. Blood and bone specimens were collected. Bone samples were pulverized under liquid nitrogen with a cryogenic mill, including an internal standard. The drug concentrations in serum and total bone were analyzed by liquid chromatography-tandem mass spectrometry. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and a target time of the non-protein-bound drug concentration above the MIC for >50% of the dosing interval for near-maximal bactericidal activity in serum. The median of the ratio of the area under the curve (AUC) for bone/AUC for serum was 20% (10th to 90th percentile for betweensubject variability [variability], 16 to 25%) in cortical bone and 18% (variability, 11 to 29%) in cancellous bone for amoxicillin and 15% (variability, 11 to 21%) in cortical bone and 10% (variability, 5.1 to 21%) in cancellous bone for clavulanic acid. Analysis in S-ADAPT yielded similar results. The equilibration half-lives between serum and bone were 12 min for amoxicillin and 14 min for clavulanic acid. For a 30-min infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid every 4 h, amoxicillin achieved robust (>90%) probabilities of target attainment (PTAs) for MICs of <12 mg/liter in serum and 2 to 3 mg/liter in bone and population PTAs above 95% against methicillin-susceptible Staphylococcus aureus in bone and serum. The AUC of amoxicillin-clavulanic acid was 5 to 10 times lower in bone than in serum, and amoxicillin-clavulanic acid achieved a rapid equilibrium and favorable population PTAs against pathogens commonly encountered in bone infections.Osteomyelitis is difficult to diagnose and treat and may cause irreversible damage. Antibiotic treatment over weeks to months is required, often in addition to surgical debridement. To reduce the incidence of infections after orthopedic surgery, perioperative prophylaxis is standard practice. Each year more than a million hip replacements are done worldwide. Prosthetic devices are particularly susceptible to infections, more than 50% of which are due to Staphylococcus aureus or coagulase-negative staphylococci, such as S. epidermidis (38). It is vitally important that adequate surgical prophylaxis be used and that sufficient concentrations of antibiotic with activity against frequently encountered pathogens in bone be achieved.Amoxicillin (amoxicilline) in combination with clavulanic acid is active against pathogens commonly found in prosthesisrelated bone infections (MICs at which 90% of bacteria are inhibited [MIC 90 s], 1 mg/liter for methicillin-susceptible S. aureus [MSSA] and 8 mg/liter for S. epidermidis [28]). Successful treat...

show abstract

Section: Vol 53 2009 Amoxicillin-clavulanic Acid Population Pk-pd 2573supporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Bone Penetration of Amoxicillin and Clavulanic Acid Evaluated by Population Pharmacokinetics and Monte Carlo Simulation

Landersdorfer

Kinzig

Bulitta

et al. 2009

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Piperacillin and tazobactam 4.52 ,ug/g for tazobactam). Our results are comparable to those for other ,-lactamase inhibitors, i.e., clavulanic acid has been reported to achieve concentrations in bone in excess of those necessary to inhibit 3-lactamases to a clinically significant extent (1,5,13). The concentration ratios of piperacillin/tazobactam in cancellous bone tissue (9.4 ± 1.8) and in cortical bone tissue (8.0 ± 2.2) were similar and were also similar to the 8:1 ratio of the two drugs administered.…”

supporting

confidence: 84%

Penetration of piperacillin-tazobactam into cancellous and cortical bone tissues

Incavo

Ronchetti

Choi

et al. 1994

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The penetration characteristics of piperacillin-tazobactam into cortical and cancellous bone tissues were investigated in 10 patients undergoing total hip replacement. The concentration ratios of piperacillin/ tazobactam were 9.4 ± 1.8 in cancellous bone tissue and 8.0 ± 2.2 in cortical bone tissue, which were close to the 8:1 ratio of drugs administered. The mean ratios of drug concentrations in bone and plasma for cancellous and cortical tissue were 23 and 18%, respectively, for piperacillin and 26 and 22%, respectively, for tazobactam. The concentrations of tazobactam achieved are sufficient to exert anti-j-lactamase activity and supportive of clinical trials involving bone and joint infections, including those caused by P-lactamase-producing pathogens.One important criterion for dose selection of an antibiotic is the degree of penetration to the infected site.Piperacillin sodium has been widely used in the treatment of serious infections, including bone and joint infections (4, 14). Its effect, however, is limited by its susceptibility to 3-lactamase inactivation. Tazobactam (CL 298, produced by piperacillin-resistant isolates, namely, Escherichia coli, Staphylococcus sp., and Bacteroides sp. (6). Since tazobactam rapidly and irreversibly inactivates ,-lactamases, maintenance of concentration above the MIC for most of the dosing interval at the site of infection as required for ,B-lactams may not be necessary. A combination of 3 g of piperacillin and 375 mg of tazobactam (an 8:1 ratio) given every 6 h as monotherapy has been efficacious for treating various infections, including bone and joint infections. This study was undertaken to characterize (i) the concentrations of tazobactam in bone and (ii) the ratio of piperacillin/tazobactam in cortical and cancellous bone tissues.This was a single-dose, open-label, single-arm, noncomparative study. Patients over the age of 18 years and weighing between 45 and 102 kg who were undergoing elective total hip replacement were enrolled in this study after an informed consent was obtained. Patients were excluded if they were allergic to 3-lactam antibiotics or ,-lactamase inhibitors, receiving any other antimicrobial therapy, or exhibited renal dysfunction defined by a creatinine clearance of <40 ml/min or a concentration of creatinine in serum of >2.5 mg/dl. Usual preoperative medications except those known to affect piperacillin-tazobactam disposition (e.g., probenecid) were allowed. Additional antibiotics were allowed after the bone and plasma sampling was completed. Recording of medical history, a physical examination, and clinical laboratory tests were

show abstract

Pharmacokinetics and Pharmacodynamics of Antibiotics in Bone

Landersdorfer

Bulitta

Sörgel

2015

Bone and Joint Infections

View full text Add to dashboard Cite

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.

show abstract

Penetration of amoxycillin/clavulanate into human bone

Cited by 22 publications

References 0 publications

Bone Penetration of Amoxicillin and Clavulanic Acid Evaluated by Population Pharmacokinetics and Monte Carlo Simulation

Bone Penetration of Amoxicillin and Clavulanic Acid Evaluated by Population Pharmacokinetics and Monte Carlo Simulation

Penetration of piperacillin-tazobactam into cancellous and cortical bone tissues

Pharmacokinetics and Pharmacodynamics of Antibiotics in Bone

Contact Info

Product

Resources

About