Revisiting Beta-lactams – PK/PD improves dosing of old antibiotics

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Pre-clinical pharmacokinetic–pharmacodynamic assessments indicate Beta-lactam antibiotics have time-dependent killing, variable persistent antibiotic effects and that free drug T > MIC is the dominant pharmacodynamic index. Prolonged or continuous infusion therapy has improved microbiological responses in pathogens with MICs at or 2–4 fold higher than existing EUCAST clinical breakpoints in pre-clinical studies. Human population pharmacokinetic modelling combined with Monte Carlo Simulation indicates improved pharmacodynamic target attainment rates and hence predicts improved clinical responses for those pathogens with raised MICs. However, the majority of human clinical trials comparing prolonged or continuous infusion to intermittent injection have failed to show superior clinical cures and for the most part microbiological successes. The exception being in various subgroup analyses. Future clinical trials need to focus on defining the T > MIC sizes associated with clinical or microbiological cure in man, on those subgroups of patients where continuous, or prolonged infusion, is likely to be of greatest benefit, seek to reduce pharmacokinetic variability by the use of therapeutic drug monitoring and include measurement of the risks of emergence of resistance in target pathogens At present, the clinical evidence base for prolonged or continuous infusion therapy is insufficiently strong to support widespread use.

Highlights

► Pre-clinical data, with Beta-lactams indicate continuous or prolonged infusion (C or PI) has advantages over conventional dosing. ► Clinical trials have failed to show consistant benefits with C or PI. ► Future trials need to translate pre-clinical data into man identifying patient groups who will most benefit from C or PI.

Introduction

The pharmacokinetics and pharmacodynamics of Beta-lactam drugs (penicillins, cephalosporins and carbapenems) have been extensively studied in pre-clinical infection models and numerous clinical studies in man. There is, therefore, a significant literature relevant to both in vitro, in vivo, in silico and human trials findings. The basic pharmacodynamic properties of Beta-lactams imply that continuous infusion or prolonged infusion therapies (see definitions – Table 1) should have bacteriological and clinical advantages over intermittent injection when treating certain pathogens or infections. The topic of continuous infusion Beta-lactam therapy has been reviewed previously [1••, 2, 3••]. In this review I will discuss the pre-clinical rationale for prolonged or continuous infusion B. lactam therapy as well as bringing the reported clinical experiences up to date. Finally, I will discuss the unresolved pre-clinical and clinical issues related to these therapeutic approaches.

Section snippets

Pre-clinical studies

The pre-clinical pharmacodynamics of Beta-lactam drugs have been well understood for over a decade [[4] (Table 2)]. Antibacterial killing owing to Beta-lactams increases as drug concentrations increase below the pathogen MIC value and up to 4–5 times above the MIC. Bacterial killing at concentrations greater than these values does not increase with Enterobacteriaceae, Staphylococcus aureus or Pseudonomas aeruginosa [5, 6]. Within the Beta-lactam family it has been proposed that penicillins,

Human pharmacokinetics

The pharmacokinetic/pharmacodynamic characteristics of continuous infusion therapy in comparison to intermittent injection have been the subject of a systematic review for all antibacterials with a time-dependent action – most of these studies were of Beta-lactams [17••]. Seventeen randomised trials comparing continuous with intermittent infusion of the same antibacterial regimen were identified. The mean peak concentrations (Cmax) of the intermittent administration was 5.5 times (range

Human clinical studies

Prolonged or continuous infusion therapy has been investigated in a range of comparative trials with conventional intermittent injection using different penicillins, cephalosporins and the carbapenem, meropenem. A range of different Gram-positive and Gram-negative pathogens have been targeted as well as use an empiric and definitive therapy in a range of healthcare settings. It remains unclear which particular patient groups benefit most from prolonged or continuous infusion therapy but our

Penicillins

Piperacilllin-tazobactam has been studied in a number of comparative trials comparing prolonged or continuous infusion to conventional dosing. Continuous infusion was compared to intermittent infusion in a group of 98 patients with mainly skin and skin structure, respiratory or intra abdominal infection and found to be superior in terms of microbiological success, more rapid resolution of fever and reduced costs. Clinical cure rates were not changed [29]. A much larger prospective randomised

Cephalosporins

The pharmacodynamics of cefepime was studied in 29 patients with documented Gram-negative bacillary infection. T > MIC was related to outcome with a microbiological success rate of 89% if the T > MIC was 100% and a cure rate of 0% of the T > MIC was <100% [33]. More recently the rate of clinical cure with ceftobiprole in skin and skin structure infection was related to a fT > MIC value of ≥30% or ≥50% [34••].

Twenty years ago Lagast et al. [35] compared continuous infusion cefoperazone to intermittent

Carbapenems

A number of studies have reported meropenem pharmacokinetic and pharmacodynamic properties when administered by continuous or prolonged infusion. However, there is very little clinical experience reported from randomised controlled trials [42]. Lorente et al. [43], performed a retrospective cohort study in patients with VAP caused by Gram-negative bacilli who were treated with meropenem by continuous infusion or intermittent injection showing cure rates were higher in those receiving continuous

Risk of emergence of resistance

Clinical pharmacodynamic studies on the impact of Beta-lactam dosing and risk of resistance are scarce. It is known that low dose prolonged treatment oral B. lactams favour the carriage of penicillin resistant Streptococcus pneumoniae in children [44]. In addition, in a randomised trial short course, high dose amoxicillin reduced the carriage of penicillin resistant S. pneumoniae compared to low dose, long duration [45]. Data comparing prolonged or continuous infusion therapy Beta-lactam to

Conclusions

Pre-clinical and human population pharmacokinetic data, combined with Monte Carlo Simulation, would predict that continuous or prolonged infusion Beta-lactams would have clinical benefit. However, the results of clinical trials comparing these modes of administration to intermittent injection most often fail to demonstrate superiority in microbiological or clinical end points. This is most probably because such trials fail to enrich for the patients most likely to see benefit and also fail to

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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