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Fulltext Prolonged administration of β-lactam antibiotics - a comprehensive review and critical appraisal

Osthoff M, Siegemund M, Balestra G, Abdul-Aziz MH, Roberts JA

Swiss Med Wkly, 2016;146:w14368.
PMID: 27731492 DOI: 10.4414/smw.2016.14368

Prolonged infusion of β-lactam antibiotics as either extended (over at least 2 hours) or continuous infusion is increasingly applied in intensive care units around the world in an attempt to optimise treatment with this most commonly used class of antibiotics, whose effectiveness is challenged by increasing resistance rates. The pharmacokinetics of β-lactam antibiotics in critically ill patients is profoundly altered secondary to an increased volume of distribution and the presence of altered renal function, including augmented renal clearance. This may lead to a significant decrease in plasma concentrations of β-lactam antibiotics. As a consequence, low pharmacokinetic/pharmacodynamic (PK/PD) target attainment, which is described as the percentage of time that the free drug concentration is maintained above the minimal inhibitory concentration (MIC) of the causative organism (fT>MIC), has been documented for β-lactam treatment in these patients when using standard intermittent bolus dosing, even for the most conservative target (50% fT>MIC). Prolonged infusion of β-lactams has consistently been shown to improve PK/PD target attainment, particularly in patients with severe infections. However, evidence regarding relevant patient outcomes is still limited. Whereas previous observational studies have suggested a clinical benefit of prolonged infusion, results from two recent randomised controlled trials of continuous infusion versus intermittent bolus administration of β-lactams are conflicting. In particular, the larger, double-blind placebo-controlled randomised controlled trial including 443 patients did not demonstrate any difference in clinical outcomes. We believe that a personalised approach is required to truly optimise β-lactam treatment in critically ill patients. This may include therapeutic drug monitoring with real-time adaptive feedback, rapid MIC determination and the use of antibiotic dosing software tools that incorporate patient parameters, dosing history, drug concentration and site of infection. Universal administration of β-lactam antibiotics as prolonged infusion, even if supported by therapeutic drug monitoring, is not yet ready for "prime time", as evidence for its clinical benefit is modest. There is a need for prospective randomised controlled trials that assess patient-centred outcomes (e.g. mortality) of a personalised approach in selected critically ill patients including prolonged infusion of β-lactams compared with the current standard of care.

Matched MeSH terms: beta-Lactams/therapeutic use*
Fulltext Community-acquired pneumonia in Malaysian patients: addition of macrolide and the use of BTS "curb" index to assess severity

Loh LC

Med J Malaysia, 2006 Mar;61(1):128-30.
PMID: 16708753

Sir, I read with interest the elegantly written CME article by Liam C K recently!. The choice of empiric antibiotic(s) in treating hospitalized adult patients with communityacquired pneumonia (CAP) is important as it can influence clinical outcomes 2. As correctly pointed out by the author, patients with CAP requiring hospitalization should, in addition to a ~-lactam stable antibiotic, be covered with a macrolide, to combat atypical pathogens such as Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae. Such is the recommendation from most foreign guidelines 3. 4. Here I wish to add our own observation based on a prospective study conducted between 2002 and 2004 of 141 adult patients with CAP hospitalized in Seremban Hospital in which we studied the clinical outcomes of patients treated empirically with and without a macrolide added to their ~-lactam stable antibiotic, recently published in Respirology 5.

Matched MeSH terms: beta-Lactams/therapeutic use*
Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. A Meta-analysis of Individual Patient Data from Randomized Trials

Roberts JA, Abdul-Aziz MH, Davis JS, Dulhunty JM, Cotta MO, Myburgh J, et al.

Am J Respir Crit Care Med, 2016 Sep 15;194(6):681-91.
PMID: 26974879 DOI: 10.1164/rccm.201601-0024OC

RATIONALE: Optimization of β-lactam antibiotic dosing for critically ill patients is an intervention that may improve outcomes in severe sepsis.
OBJECTIVES: In this individual patient data meta-analysis of critically ill patients with severe sepsis, we aimed to compare clinical outcomes of those treated with continuous versus intermittent infusion of β-lactam antibiotics.
METHODS: We identified relevant randomized controlled trials comparing continuous versus intermittent infusion of β-lactam antibiotics in critically ill patients with severe sepsis. We assessed the quality of the studies according to four criteria. We combined individual patient data from studies and assessed data integrity for common baseline demographics and study endpoints, including hospital mortality censored at 30 days and clinical cure. We then determined the pooled estimates of effect and investigated factors associated with hospital mortality in multivariable analysis.
MEASUREMENTS AND MAIN RESULTS: We identified three randomized controlled trials in which researchers recruited a total of 632 patients with severe sepsis. The two groups were well balanced in terms of age, sex, and illness severity. The rates of hospital mortality and clinical cure for the continuous versus intermittent infusion groups were 19.6% versus 26.3% (relative risk, 0.74; 95% confidence interval, 0.56-1.00; P = 0.045) and 55.4% versus 46.3% (relative risk, 1.20; 95% confidence interval, 1.03-1.40; P = 0.021), respectively. In a multivariable model, intermittent β-lactam administration, higher Acute Physiology and Chronic Health Evaluation II score, use of renal replacement therapy, and infection by nonfermenting gram-negative bacilli were significantly associated with hospital mortality. Continuous β-lactam administration was not independently associated with clinical cure.
CONCLUSIONS: Compared with intermittent dosing, administration of β-lactam antibiotics by continuous infusion in critically ill patients with severe sepsis is associated with decreased hospital mortality.

Matched MeSH terms: beta-Lactams/therapeutic use
Extended Spectrum Beta-lactamases: Definition, Classification and Epidemiology

Ghafourian S, Sadeghifard N, Soheili S, Sekawi Z

Curr Issues Mol Biol, 2015;17:11-21.
PMID: 24821872

Extended spectrum beta-lactamases (ESBLs) are defined as enzymes produced by certain bacteria that are able to hydrolyze extended spectrum cephalosporin. They are therefore effective against beta-lactam antibiotics such as ceftazidime, ceftriaxone, cefotaxime and oxyimino-monobactam. The objective of the current review is to provide a better understanding of ESBL and the epidemiology of ESBL producing organisms which are among those responsible for antibiotic resistant strains. Globally, ESBLs are considered to be problematic, particularly in hospitalized patients. There is an increasing frequency of ESBL in different parts of the world. The high risk patients are those contaminated with ESBL producer strains as it renders treatment to be ineffective in these patients. Thus, there an immediate needs to identify EBSL and formulate strategic policy initiatives to reduce their prevalence.

Matched MeSH terms: beta-Lactams/therapeutic use
Continuous infusion vs. bolus dosing: implications for beta-lactam antibiotics

Mohd Hafiz AA, Staatz CE, Kirkpatrick CM, Lipman J, Roberts JA

Minerva Anestesiol, 2012 Jan;78(1):94-104.
PMID: 21730935

Beta-lactam antibiotics display time-dependant pharmacodynamics whereby constant antibiotic concentrations rather than high peak concentrations are most likely to result in effective treatment of infections caused by susceptible bacteria. Continuous administration has been suggested as an alternative strategy, to conventional intermittent dosing, to optimise beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) properties. With the availability of emerging data, we elected to systematically investigate the published literature describing the comparative PK/PD and clinical outcomes of beta-lactam antibiotics administered by continuous or intermittent infusion. We found that the studies have been performed in various patient populations including critically ill, cancer and cystic fibrosis patients. Available in vitro PK/PD data conclusively support the administration of beta-lactams via continuous infusion for maximizing bacterial killing from consistent attainment of pharmacodynamic end-points. In addition, clinical outcome data supports equivalence, even with the use of a lower dose by continuous infusion. However, the present clinical data is limited with small sample sizes common with insufficient power to detect advantages in favour of either dosing strategy. With abundant positive pre-clinical data as well as document in vivo PK/PD advantages, large multi-centre trials are needed to describe whether continuous administration of beta-lactams is truly more effective than intermittent dosing.

Matched MeSH terms: beta-Lactams/therapeutic use