***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: A prospect i ve , r and omized pilot study was undertaken to compare the efficacy of continuous versus intermittent ceftazidime in ICU patients with nosocomial pneumonia .  Ceftazidime was administered either as a 3 g/day continuous infusion ( CI ) or an intermittent infusion ( II ) of 2 g every 8 h. In addition , all patients received concomitant once-daily tobramycin . The demographics of the evaluable patients ( n = 35 ) were similar between the groups : age ( years ) , CI 46 + /- 16 , II 56 + /- 20 ; Apache score , CI 14 + /- 4 , II 16 + /- 6 ; time ( days ) from admission to diagnosis , CI 9 + /- 6 , II 9 + /- 6 .  Clinical efficacy , defined as cure/improvement was similar between groups [ n ( % ) , CI 16/17 ( 94 ) , II 15/18 ( 83 ) ] , while microbiological response was also comparable [ n ( % ) , CI 10/13 ( 76 ) , II 12/15 ( 80 ) ] . Minimal inhibitory concentrations ( MICs ) for all isolates were measured throughout the treatment course ; there was no development of resistance during therapy for either regimen . While limited clinical data exist , our results suggest that the use of ceftazidime by CI administration maintains clinical efficacy , optimizes the pharmacodynamic profile and uses less antibiotic compared with the st and ard 2 g every 8 h intermittent dosing regimen OBJECTIVES To compare the plasma and subcutaneous tissue concentration-time profiles of meropenem administered by intermittent bolus dosing or continuous infusion to critically ill patients with sepsis and without renal dysfunction , and to use population pharmacokinetic modelling and Monte Carlo simulations to assess the cumulative fraction of response ( CFR ) against Gram-negative pathogens likely to be encountered in critical care units . PATIENTS AND METHODS We r and omized 10 patients with sepsis to receive meropenem  by intermittent bolus administration ( n = 5 ; 1 g 8 hourly ) or an equal dose administered by continuous infusion ( n = 5 ) . Serial subcutaneous tissue concentrations were determined using microdialysis and compared with plasma data for first-dose and steady-state pharmacokinetics . Population pharmacokinetic modelling of plasma data and Monte Carlo simulations were then undertaken with NONMEM . RESULTS It was found that continuous infusion maintains higher median trough concentrations , in both plasma ( intermittent bolus 0 versus infusion 7 mg/L ) and subcutaneous tissue ( 0 versus 4 mg/L ) . All simulated intermittent bolus , extended and continuous infusion dosing achieved 100 % of pharmacodynamic targets against most Gram-negative pathogens . Superior obtainment of pharmacodynamic targets was achieved using administration by extended or continuous infusion against less susceptible Pseudomonas aeruginosa and Acinetobacter species . CONCLUSIONS This is the first study to compare the relative concentration-time data of bolus and continuous administration of meropenem at the subcutaneous tissue and plasma levels . We found that the administration of meropenem by continuous infusion maintains higher concentrations in subcutaneous tissue and plasma than by intermittent bolus dosing . Administration by extended or continuous infusion will achieve superior CFR against less-susceptible organisms in patients without renal dysfunction 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 prospect i ve 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+/-st and ard 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 result ed 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 Introduction Meropenem bactericidal activity depends on the time when the free drug concentrations remain above the minimum inhibitory concentration of pathogens . The goal of this study was to compare clinical and bacteriological efficacy of continuous meropenem infusion versus bolus administration in critically ill patients with severe infection , and to evaluate the safety of both dosing regimens . Methods Patients admitted to the interdisciplinary Intensive Care Unit ( ICU ) who suffered from severe infections and received meropenem were r and omized either in the Infusion group ( n = 120 ) or in the Bolus group ( n = 120 ) . Patients in the Infusion group received a loading dose of 2 g of meropenem followed by a continuous infusion of 4 g of meropenem over 24 hours . Patients in the Bolus group were given 2 g of meropenem over 30 minutes every 8 hours . Clinical and microbiological outcome , safety , meropenem-related length of ICU and hospital stay , meropenem-related length of mechanical ventilation , duration of meropenem treatment , total dose of meropenem , and ICU and in-hospital mortality were assessed . Results Clinical cure at the end of meropenem therapy was comparable between both groups ( 83.0 % patients in the Infusion vs. 75.0 % patients in the Bolus group ; P = 0.180 ) . Microbiological success rate was higher in the Infusion group as opposed to the Bolus group ( 90.6 % vs. 78.4 % ; P = 0.020 ) . Multivariate logistic regression identified continuous administration of meropenem as an independent predictor of microbiological success ( OR = 2.977 ; 95 % CI = 1.050 to 8.443 ; P = 0.040 ) . Meropenem-related ICU stay was shorter in the Infusion group compared to the Bolus group ( 10 ( 7 to 14 ) days vs. 12 ( 7 to 19 ) days ; P = 0.044 ) as well as shorter duration of meropenem therapy ( 7 ( 6 to 8) days vs. 8 ( 7 to 10 ) days ; P = 0.035 ) and lower total dose of meropenem ( 24 ( 21 to 32 ) grams vs. 48 ( 42 to 60 ) grams ; P < 0.0001 ) . No severe adverse events related to meropenem administration in either group were observed . Conclusions Continuous infusion of meropenem is safe and , in comparison with higher intermittent dosage , provides equal clinical outcome , generates superior bacteriological efficacy and offers encouraging alternative of antimicrobial therapy in critically ill patients Introduction Cefepime has been associated with a greater risk of mortality than other beta-lactams in patients treated for severe sepsis . Hypotheses for this failure include possible hidden side-effects ( for example , neurological ) or inappropriate pharmacokinetic/pharmacodynamic ( PK/PD ) parameters for bacteria with cefepime minimal inhibitory concentrations ( MIC ) at the highest limits of susceptibility ( 8 mg/l ) or intermediate-resistance ( 16 mg/l ) for pathogens such as Enterobacteriaceae , Pseudomonas aeruginosa and Staphylococcus aureus . We examined these issues in a prospect i ve non-interventional study of 21 consecutive intensive care unit ( ICU ) adult patients treated with cefepime for nosocomial pneumonia . Methods Patients ( median age 55.1 years , range 21.8 to 81.2 ) received intravenous cefepime at 2 g every 12 hours for creatinine clearance ( CLCr ) ≥ 50 ml/min , and 2 g every 24 hours or 36 hours for CLCr < 50 ml/minute . Cefepime plasma concentrations were determined at several time-points before and after drug administration by high-pressure liquid chromatography . PK/PD parameters were computed by st and ard non-compartmental analysis . Results Seventeen first-doses and 11 steady states ( that is , four to six days after the first dose ) were measured . Plasma levels varied greatly between individuals , from two- to three-fold at peak-concentrations to up to 40-fold at trough-concentrations . Nineteen out of 21 ( 90 % ) patients had PK/PD parameters comparable to literature values . Twenty-one of 21 ( 100 % ) patients had appropriate duration of cefepime concentrations above the MIC ( T > MIC ≥ 50 % ) for the pathogens recovered in this study ( MIC ≤ 4 mg/l ) , but only 45 to 65 % of them had appropriate coverage for potential pathogens with cefepime MIC ≥ 8 mg/l . Moreover , 2/21 ( 10 % ) patients with renal impairment ( CLCr < 30 ml/minute ) demonstrated accumulation of cefepime in the plasma ( trough concentrations of 20 to 30 mg/l ) in spite of dosage adjustment . Both had symptoms compatible with non-convulsive epilepsy ( confusion and muscle jerks ) that were not attributed to cefepime-toxicity until plasma levels were disclosed to the caretakers and symptoms resolved promptly after drug arrest . Conclusions These empirical results confirm the suspected risks of hidden side-effects and inappropriate PK/PD parameters ( for pathogens with upper-limit MICs ) in a population of ICU adult patients . Moreover , it identifies a safety and efficacy window for cefepime doses of 2 g every 12 hours in patients with a CLCr ≥ 50 ml/minute infected by pathogens with cefepime MICs ≤ 4 mg/l . On the other h and , prompt monitoring of cefepime plasma levels should be considered in case of lower CLCr or greater MICs ABSTRACT The pharmacokinetics of imipenem were studied in adult intensive care unit ( ICU ) patients during continuous venovenous hemofiltration ( CVVH ; n = 6 patients ) or hemodiafiltration ( CVVHDF ; n = 6 patients ) . Patients ( mean ± st and ard deviation age , 50.9 ± 15.9 years ; weight , 98.5 ± 15.9 kg ) received imipenem at 0.5 g every 8 to 12 h ( total daily doses of 1 to 1.5 g/day ) by intravenous infusion over 30 min . Pre- and postmembrane blood ( plasma ) and corresponding ultrafiltrate or dialysate sample s were collected 1 , 2 , 4 , and 8 or 12 h ( depending on dosing interval ) after completion of the drug infusion . Drug concentrations were measured using vali date d high-performance liquid chromatography methods . Mean systemic clearance ( CLS ) and elimination half-life ( t1/2 ) of imipenem were 145 ± 18 ml/min and 2.7 ± 1.3 h during CVVH versus 178 ± 18 ml/min and 2.6 ± 1.6 h during CVVHDF , respectively . Imipenem clearance was substantially increased during both CVVH and CVVHDF , with membrane clearance representing 25 % and 32 % of CLS , respectively . The results of this study indicate that CVVH and CVVHDF contribute to imipenem clearance to a greater degree than previously reported . Imipenem doses of 1.0 g/day appear to achieve concentrations adequate to treat most common gram-negative pathogens ( MIC up to 2 μg/ml ) during CVVH or CVVHDF , but doses of 2.0 g/day or more may be required to adequately treat and prevent resistance in pathogens with higher MICs ( MIC = 4 to 8 μg/ml ) . Higher doses should only be used after consideration of potential central nervous system toxicities or other risks of therapy in these severely ill patients BACKGROUND Beta-lactam antibiotics are a commonly used treatment for severe sepsis , with intermittent bolus dosing st and ard therapy , despite a strong theoretical rationale for continuous administration . The aim of this trial was to determine the clinical and pharmacokinetic differences between continuous and intermittent dosing in patients with severe sepsis . METHODS This was a prospect i ve , double-blind , r and omized 
    Output:
    
Conclusions Pooled results from small RCTs suggest reduced clinical failure rates and intensive care unit length-of-stay when using continuous/extended infusions of antibiotics in critically ill patients  .
Reduced mortality rates almost achieved statistical significance when the results of RCTs were combined with cohort studies .
These results support the conduct of adequately powered RCTs to define better the utility of continuous/extended infusions in the era of antibiotic resistance