Pharmacokinetic and Pharmacodynamic Analysis of Ceftazidime/Avibactam in Critically Ill Patients.

BACKGROUND: The pharmacokinetics, especially the volume of distribution (Vd), of ß-lactam antibiotics can be altered in critically ill patients. This can lead to decreased serum concentrations and a reduction in clinical cures. Ceftazidime/avibactam (CZA) is a new antimicrobial agent utilized in critically ill patients although its pharmacokinetics has not been well defined in these patients. PATIENTS AND METHODS: In this study, the serum concentrations of CZA from adult patients treated in an intensive care unit (ICU) with standard dosing regimens were measured and both pharmacokinetic and pharmacodynamic parameters were computed. The pharmacodynamic analyses included Monte Carlo simulations to determine the probability of target attainment (PTA: free ceftazidime concentrations exceed the minimum inhibitory concentration [MIC] for 50% of the dosing interval; free avibactam concentrations exceed 1 mg/L over the dosing interval) and serum time-kill curves against multi-drug-resistant Enterobacteriaceae susceptible to CZA. Serum concentrations were measured in 10 critically ill patients at two, four, six, and eight hours after multiple doses (infused over two hours) of CZA. RESULTS: A significant linear relation between creatinine clearance and total body clearance was identified for both ceftazidime (R = 0.91) and avibactam (R = 0.88). The mean clearance, volume of distribution, and half-life for ceftazidime were 6.1 ± 3.8 L/h, 35 ± 10.5 L, and 4.8 ± 2.15 h, respectively. For avibactam, these values were 11.1 ± 6.8 L/h, 50.8 ± 14.3 L, and 4.1 ± 2.1 h, respectively. Ceftazidime/avibactam achieved optimal PTA for bacteria with MICs of 16 mg/L or less. Furthermore, time-kill experiments revealed that serum concentrations of CZA, at each collection time, exhibited bactericidal (≥ 3 log10 CFU/mL reduction) activity against each of the study isolates. CONCLUSION: In conclusion, our study results suggest that the current dosing regimens of CZA can provide effective antimicrobial activity in ICU patients against CZA-susceptible (MIC ≤8 mg/L) isolates.

On the Relationship between Safety and Decision Significance.

Risk analysts are often concerned with identifying key safety drivers, that is, the systems, structures, and components (SSCs) that matter the most to safety. SSCs importance is assessed both in the design phase (i.e., before a system is built) and in the implementation phase (i.e., when the system has been built) using the same importance measures. However, in a design phase, it would be necessary to appreciate whether the failure/success of a given SSC can cause the overall decision to change from accept to reject (decision significance). This work addresses the search for the conditions under which SSCs that are safety significant are also decision significant. To address this issue, the work proposes the notion of a θ-importance measure. We study in detail the relationships among risk importance measures to determine which properties guarantee that the ranking of SSCs does not change before and after the decision is made. An application to a probabilistic safety assessment model developed at NASA illustrates the risk management implications of our work.

Tissue penetration and antimicrobial activity of standard- and high-dose trimethoprim/sulfamethoxazole and linezolid in patients with diabetic foot infection.

OBJECTIVES: The purpose of this study was to conduct a pharmacokinetic and pharmacodynamic evaluation of high (320/1600 mg) and standard (160/800 mg) doses of trimethoprim/sulfamethoxazole and linezolid in outpatients with mild diabetic foot infections (DFIs). METHODS: Both viable skin/soft tissue from the infection site and serum were obtained at various times after antibiotic administration from 18 patients (6 per study group) being treated with linezolid, standard doses of trimethoprim/sulfamethoxazole or high doses of trimethoprim/sulfamethoxazole during a follow-up clinic visit. These samples were assayed for drug concentrations by liquid chromatography in tandem with mass spectrometry. Patient sera were also utilized in time-kill assays against two strains of Staphylococcus aureus and three strains of ß-haemolytic streptococci. RESULTS: The mean tissue/serum ratio for linezolid was 0.46 (range, 0.18-0.71). The mean tissue/serum ratio for trimethoprim was 1.2 (range, 0.3-4.5) for both standard and high doses, and 0.23 (range, 0.1-0.46) and 0.36 (range, 0.14-1.28) for standard and high doses of sulfamethoxazole, respectively. Linezolid exhibited inhibitory activity in time-kill assays against strains of S. aureus (0.45 ± 0.5 log10 cfu/mL) and ß-haemolytic streptococci (2.2 ± 0.6 log10 cfu/mL), while trimethoprim/sulfamethoxazole exhibited bactericidal (>3 log kill) activity against all of these isolates. These findings were consistent for each sampling time and for high as well as standard doses of trimethoprim/sulfamethoxazole. CONCLUSIONS: This pharmacokinetic/pharmacodynamic study found that trimethoprim/sulfamethoxazole exhibits good skin/soft tissue penetration in patients with DFIs as well as bactericidal activity in serum against strains of S. aureus and ß-haemolytic streptococci.

Pharmacokinetics and monte carlo simulations of doripenem in patients with febrile neutropenia.

BACKGROUND: Doripenem is a group 2 carbapenem with enhanced in vitro activity against gram-negative bacteria including Pseudomonas aeruginosa. There is a paucity of pharmacokinetic/pharmacodynamic data on doripenem in patients with febrile neutropenia. OBJECTIVE: To conduct a pharmacokinetic evaluation of 2 doses of doripenem in patients with febrile neutropenia and provide probability estimates of attaining effective drug exposure against common gram-negative pathogens. METHODS: We obtained multiple blood samples from 12 adults with febrile neutropenia who were receiving either 500 mg or 1000 mg of intravenous doripenem over 4 hours every 8 hours. Following at least 2 doses, serum concentrations were measured in each subject at 1, 4, 6, and 8 hours after initiation of a dose by a validated high-performance liquid chromatography assay. The derived pharmacokinetic parameters from these serum levels were used to perform a 5000-patient Monte Carlo simulation against bacteria with minimal inhibitory concentrations (MICs) of 0.008-64 mg/L to determine probability estimates of the time in which unbound drug concentrations remain above the MIC (fT(>MIC)). RESULTS: The mean pharmacokinetic parameters in these patients were a volume of distribution of 43.9 L, an elimination rate constant of 0.37 h(-1), a total clearance of 14.4 L/h, and an area under the concentration-time curve of 57.6 mg•h/L. An optimal probability of target attainment (40% fT(>MIC)) of 90% was obtained against bacteria with MICs ≤2 mg/L and ≤4 mg/L with 500-mg and 1000-mg doses, respectively. Adverse events associated with doripenem were not observed. CONCLUSIONS: The findings from this analysis of doripenem suggest that higher doses, as well as prolonged infusions, may be necessary to optimally treat selected gram-negative bacteria (eg, P. aeruginosa) in patients with febrile neutropenia.

Tigecycline penetration into skin and soft tissue.

BACKGROUND: Tigecycline, a derivative of minocycline, has antibacterial activity against common pathogens associated with complicated skin and soft tissue infections (cSSTIs), including methicillin-resistant Staphylococcus aureus. At present, there is a paucity of data concerning its penetration into skin and soft tissue (SST). METHODS: This study evaluated the penetration of tigecycline into SST in 25 patients (mean age, 52 years) with cSSTIs requiring surgical intervention. After a 100-mg loading dose, each patient received 50 mg of tigecycline infused intravenously over 1 h every 12 h. Blood samples were obtained on the day of surgery at 1 h (peak), during surgery, and 12 h (trough) after the beginning of a 50-mg infusion. A viable SST sample was harvested at the infection site. Tissue and concomitant serum concentrations were grouped into three time intervals: 2-4 h (median, 3 h), 5-7 h (median, 7 h), and 8-10 h (median, 9h), and analyzed for tissue penetration. RESULTS: Tissue and blood samples were obtained one to six days (mean 2.5 days) after initiation of tigecycline treatment. The mean serum peak and trough concentrations of tigecycline were 0.56±0.25 mg/L and 0.26±0.12 mg/L, respectively. The mean tissue:serum ratios at the three study time periods were 3.8 (range 0.7-5.5), 5.2 (range 0.8-7.1), and 2.8 (range 0.8-8.8). CONCLUSIONS: In general, we found higher concentrations of tigecycline in SST than in the serum at the same time point.

The effect of creatine intake on renal function.

OBJECTIVE: To examine the effect of creatine supplementation on renal function and estimates of creatinine clearance. DATA SOURCES: A MEDLINE search was conducted (1966-September 2004) using the key terms creatine, creatinine, kidney function tests, drug toxicity, and exercise. Relevant articles were cross-referenced to screen for additional information. DATA SYNTHESIS: Supplementation with creatine, an unregulated dietary substance, is increasingly common in young athletes. To date, few studies have evaluated the impact of creatine on renal function and estimates of creatinine clearance. Because creatine is converted to creatinine in the body, supplementation with large doses of creatine may falsely elevate creatinine concentrations. Five studies have reported measures of renal function after acute creatine ingestion and 4 after chronic ingestion. All of these studies were completed in young healthy populations. Following acute ingestion (4-5 days) of large amounts of creatine, creatinine concentrations increased slightly, but not to a clinically significant concentration. Creatinine is also only minimally affected by longer creatine supplementation (up to 5.6 y). CONCLUSIONS: Creatine supplementation minimally impacts creatinine concentrations and renal function in young healthy adults. Although creatinine concentrations may increase after long periods of creatine supplementation, the increase is extremely limited and unlikely to affect estimates of creatinine clearance and subsequent dosage adjustments. Further studies are required in the elderly and patients with renal insufficiency.

Viral load as a surrogate end point in HIV disease.

OBJECTIVE: To examine the role of viral load as a surrogate end point for HIV disease progression and death. DATA SOURCES: A MEDLINE search was conducted for the years 1990-March 2001. In addition, relevant articles were cross-referenced to screen for additional information. STUDY SELECTION AND DATA EXTRACTION: Data regarding the validity of viral load as a surrogate end point for disease progression or death are cited. Emphasis was placed on randomized, controlled trials, but descriptive studies are also included. DATA SYNTHESIS: Recently, viral load has emerged as an important biomarker for monitoring HIV disease and antiretroviral therapy. Both baseline viral load and changes in viral load with time predict HIV disease progression and death. In fact, disease progression increases consistently once viral load exceeds 10,000 copies/mL, and AIDS and death primarily occur in patients with viral loads > 100,000 copies/mL. Changes that occur in viral load after initiation of antiretroviral therapy, however, do not fully explain the entire treatment effect. Also, separate comparisons of antiretroviral regimens may demonstrate similar differences in viral load changes but not similar differences in disease progression. CONCLUSIONS: Viral load is an important monitoring parameter for HIV disease and antiretroviral therapy. However, changes in viral load do not explain the entire clinical improvement that occurs after initiation of therapy. Although viral load is a clinically important surrogate end point for HIV disease, it cannot fully account for all associated treatment effects.