ß-Lactam pharmacodynamics in Gram-negative bloodstream infections in the critically ill.

OBJECTIVES: To determine the ß-lactam exposure associated with positive clinical outcomes for Gram-negative blood stream infection (BSI) in critically ill patients. PATIENTS AND METHODS: Pooled data of critically ill patients with mono-microbial Gram-negative BSI treated with ß-lactams were collected from two databases. Free minimum concentrations (fCmin) of aztreonam, cefepime, ceftazidime, ceftriaxone, piperacillin (co-administered with tazobactam) and meropenem were interpreted in relation to the measured MIC for targeted bacteria (fCmin/MIC). A positive clinical outcome was defined as completion of the treatment course or de-escalation, without other change of antibiotic therapy, and with no additional antibiotics commenced within 48 h of cessation. Drug exposure breakpoints associated with positive clinical outcome were determined by classification and regression tree (CART) analysis. RESULTS: Data from 98 patients were included. Meropenem (46.9%) and piperacillin/tazobactam (36.7%) were the most commonly prescribed antibiotics. The most common pathogens were Escherichia coli (28.6%), Pseudomonas aeruginosa (19.4%) and Klebsiella pneumoniae (13.3%). In all patients, 87.8% and 71.4% achieved fCmin/MIC ≥1 and fCmin/MIC >5, respectively. Seventy-eight patients (79.6%) achieved positive clinical outcome. Two drug exposure breakpoints were identified: fCmin/MIC >1.3 for all ß-lactams (predicted difference in positive outcome 84.5% versus 15.5%, P < 0.05) and fCmin/MIC >4.95 for meropenem, aztreonam or ceftriaxone (predicted difference in positive outcome 97.7% versus 2.3%, P < 0.05). CONCLUSIONS: A ß-lactam fCmin/MIC >1.3 was a significant predictor of a positive clinical outcome in critically ill patients with Gram-negative BSI and could be considered an antibiotic dosing target.

Therapeutic drug monitoring of ß-lactam antibiotics in the critically ill: direct measurement of unbound drug concentrations to achieve appropriate drug exposures.

Objectives: To describe the achievement of unbound ß-lactam antibiotic concentration targets in a therapeutic drug monitoring (TDM) programme in critically ill patients, and the factors associated with failure to achieve a target concentration. Patients and methods: Plasma samples and clinical data were obtained for analysis from a single centre prospectively. Unbound concentrations of ceftriaxone, cefazolin, meropenem, ampicillin, benzylpenicillin, flucloxacillin and piperacillin were directly measured using ultracentrifugation. Factors associated with the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets or negative clinical outcomes were evaluated with binomial logistic regression. Results: TDM data from 330 patients, and 369 infection episodes, were included. The range of doses administered was 99.4% ± 45.1% relative to a standard daily dose. Dose increases were indicated in 33.1% and 63.4% of cases to achieve PK/PD targets of 100% fT>MIC and 100% fT>4×MIC, respectively. Dose reduction was indicated in 17.3% of cases for an upper PK/PD threshold of 100% fT>10×MIC. Higher protein bound ß-lactams (ceftriaxone and benzylpenicillin) had better therapeutic target attainment (P < 0.01), but were prone to excessive dosing. Augmented renal clearance (calculated CLCR >130 mL/min) increased the odds of failure to achieve 100% fT>MIC and 100% fT>4×MIC (OR 2.47 and 3.05, respectively; P < 0.01). Conclusions: Measuring unbound concentrations of ß-lactams as part of a routine TDM programme is feasible and demonstrates that a large number of critically ill patients do not achieve predefined PK/PD targets. The clinical significance of this finding is unknown due to the lack of correlation between PK/PD findings and clinical outcomes.

Lead Toxicity: an Australian Perspective.

Plumbism refers to the clinical features of lead toxicity, a condition which has been identified and then forgotten in a depressingly cyclical fashion since ancient times. For the past 6000 years antiquarians have described the human use of lead despite the well documented and severe adverse effects of exposure. As the analytical methods of lead measurement bring improved detection capability, it is clear that there is no safe amount of lead in the body. Sadly, we continue to identify affected patients in contemporary Australia, including young children. While there is little evidence that chelation therapy improves outcomes in affected individuals, it is recommended for use in patients with acute encephalopathy or in those with particularly elevated levels. The paucity of evidence supporting active treatment of plumbism highlights the importance of primary prevention, particularly in our most vulnerable.

Impact of ß-lactam antibiotic therapeutic drug monitoring on dose adjustments in critically ill patients undergoing continuous renal replacement therapy.

The objective of this study was to describe the effect of therapeutic drug monitoring (TDM) and dose adjustments of ß-lactam antibiotics administered to critically ill patients undergoing continuous renal replacement therapy (CRRT) in a 30-bed tertiary intensive care unit (ICU). ß-Lactam TDM data in our tertiary referral ICU were retrospectively reviewed. Clinical, demographic and dosing data were collected for patients administered ß-lactam antibiotics while undergoing CRRT. The target trough concentration range was 1-10× the minimum inhibitory concentration (MIC). A total of 111 TDM samples from 76 patients (46 male) with a mean ± standard deviation age of 56.6 ± 15.9 years and weight of 89.1 ± 25.8 kg were identified. The duration of antibiotic therapy was between 2 days and 42 days. TDM identified a need for dose modification of ß-lactam antibiotics in 39 (35%) instances; in 27 (24%) samples, TDM values resulted in decreasing the prescribed dose of ß-lactam antibiotic whereas an increase in the prescribed dose occurred in 12 (11%) cases. In patients treated for hospital-acquired pneumonia and primary or secondary bacteraemia, the dose was required to be decreased in 10/25 (40%) and 7/46 (15%) cases, respectively, to attain target concentrations. ß-Lactam TDM is a useful tool for guiding drug dosing in complex patients such as those receiving CRRT. Although over one-third of patients manifested concentrations outside the therapeutic range, most of these CRRT patients had excessive ß-lactam concentrations.

Even high-dose extended infusions may not yield desired concentrations of ß-lactams: the value of therapeutic drug monitoring.

A 35-year-old patient in intensive care with severe burn injury developed episodes of sepsis. Blood culture yielded a multidrug-resistant Pseudomonas aeruginosa and treatment was commenced with amikacin (minimum inhibitory concentration (MIC) 2-4 mg/L, dose 20 mg/kg adjusted body weight 24-hourly) and meropenem (MIC 8 mg/L, dose 2 g IV 8-hourly and later 6-hourly). Despite the use of extended infusions with ß-lactam therapeutic drug monitoring and doses that were more than 2.5 times higher than standard meropenem doses, resistance emerged. This case report describes the application of therapeutic drug monitoring to optimize ß-lactam therapy in a difficult-to-treat critically ill patient.

Therapeutic drug monitoring of beta-lactam antibiotics in burns patients--a one-year prospective study.

BACKGROUND: Beta-lactams are first-line antibiotics for the management of superficial infections due to burn injury. There is sparse data available on therapeutic drug monitoring (TDM) in patients with burns in a ward setting. This study was conducted to evaluate the utility of a beta-lactam TDM program in a cohort of burn injury patients in a ward environment. METHODS: Steady-state blood samples were collected immediately before a scheduled dose. The therapeutic concentration targets assessed were (1) free antibiotic concentrations exceeding the minimum inhibitory concentration (MIC; fT > MIC) and (2) free concentrations ≥4× MIC of the known or suspected pathogen (fT > 4× MIC). The duration of therapy was also assessed. RESULTS: A total of 50 patients were included for TDM over a 12-month period. The mean (±SD) age was 49 ± 16 years. The mean percent total body surface area burn was 17 ± 13%. The mean serum creatinine concentration was 86 ± 20 µmole/L. Sixty percent of the patients did not achieve fT > MIC, and only 18% achieved the higher target of fT > 4× MIC. Although all the patients achieved a positive clinical outcome, the duration of antibiotic treatment was shorter in patients who achieved fT > MIC compared with those who did not (4.2 ± 1.1 versus 5.3 ± 2.3 days; P = 0.03). CONCLUSIONS: We found TDM to be a reliable intervention for burn injury patients in a ward environment. This study supports pharmacokinetic data that burns patients may be at risk of subtherapeutic dosing, which may prolong the duration of antibiotic therapy.

Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept.

The extreme pharmacokinetic behaviour of drugs sometimes observed in critically ill patients poses a significant threat to the achievement of optimal antibiotic treatment outcomes. Scant information on beta-lactam antibiotic therapeutic drug monitoring (TDM) is available. The objective of this prospective study was to evaluate the practicality and utility of a beta-lactam TDM programme in critically ill patients. TDM was performed twice weekly on all eligible patients at a 30-bed tertiary referral critical care unit. Blood concentrations were determined by fast-throughput high-performance liquid chromatography (HPLC) assays and were available within 12h of sampling. Dose adjustment was instituted if the trough or steady-state blood concentration was below 4-5x the minimum inhibitory concentration (MIC) or above 10x MIC. A total of 236 patients were subject to TDM over an 11-month period. The mean+/-standard deviation age was 53.5+/-18.3 years. Dose adjustment was required in 175 (74.2%) of the patients, with 119 of these patients (50.4%) requiring dose increases after the first TDM. For outcome of therapy, 206 (87.3%) courses resulted in a positive treatment outcome and there were 30 (12.7%) treatment failures observed including 14 deaths and 15 courses requiring escalation to broader-spectrum agents; 1 course was ceased due to an adverse drug reaction. Using binomial logistic regression, only an elevated Acute Physiology and Chronic Health Evaluation (APACHE) II score (P<0.01) and elevated plasma creatinine concentration (P=0.05) were found to be predictive of mortality. In conclusion, further research is required to determine definitively whether achievement of optimal beta-lactam pharmacodynamic targets improves clinical outcomes.