By Thomas C. Neal, PharmD

According to a meta-analysis of randomized trials, prolonged infusions of antipseudomonal beta-lactam antibiotics could save lives. However, obstacles to implementing pharmacodynamically optimized administration practices have slowed the adoption of this practice in most ICUs:1

The requirement for IV pumps, preferably smart IV pumps, is potentially problematic in resource-limited settings or on wards with higher patient-to-nurse ratios than typical ICUs.
Beta-lactams tend to harbor extensive IV incompatibilities with common medications. In particular, antipseudomonal beta-lactams are incompatible with so many agents that multiple lines will be an absolute necessity for patients requiring other IV medications while undergoing prolonged infusions.
Furthermore, interpretations of the stability of beta-lactams in various diluents varies widely between different studies. For example, the package insert for meropenem admixed in 0.9% saline states that it is stable at room temperature for one hour whereas Patel and Cook reported stability of up to four hours at room temperature.2,3
It was also noted that many beta-lactams still lack data or consensus regarding optimal prolonged infusion strategies and the companies involved in their development and manufacture are unlikely to foot the bill for these studies in defense of the almighty bottom line.

Despite these barriers, the evidence suggests that the mortality benefits may warrant considering pharmacodynamically optimized beta-lactam dosing in adequately resourced ICUs. The aforementioned obstacles notwithstanding, there are definite advantages of prolonged infusion beta-lactams, and also knowledge gaps, that should be noted when implementing these dosing strategies.

Extended Antibiotic Infusions: The Theory Behind the Concept

Any discussion of prolonged infusion beta-lactams will likely begin with “why bother?” If that question cannot be answered simply, it is likely to be a very short discussion. Antibiotics possess at least one of three pharmacodynamic indices detailing the optimal pharmacokinetic targets to maximize their effects. Thankfully for this discussion, beta-lactams have the least complicated and easiest to measure pharmacodynamic profile. Bactericidal activity is achieved when the concentration of unbound beta-lactam in plasma is above a pathogen’s minimum inhibitory concentration for extended periods of time. This pharmacodynamic target is termed the “free time over MIC” or fT > MIC. The longer that drug concentrations exceed a pathogen’s MIC over the dosing interval, the longer the duration of bactericidal effect. This concept has been further scrutinized to deduce that each class of beta-lactam has unique ranges for the percent of time they should exceed the MIC to be maximally effective. For carbapenems, at least 40% of the dosing interval should exceed the MIC, 50% for penicillins, and 60%-70% for cephalosporins. Struggling with the reality that drug level monitoring for beta-lactams is woefully uncommon and most of us lack a graphing calculator in our white coats, the solution to maximizing the time above MIC is to just shoot for as long as possible, which theoretically can be achieved with extended and continuous infusions. Compared to usual IV bolus infusions that last from anywhere between one and 30 minutes, extended infusions are delivered over hours and continuous infusions are exactly that: continuous, usually over 24 hours, or for the duration of time that the beta-lactam is stable in solution.

One Infusion to Rule Them All?

The primary strategies of maximizing the fT > MIC have been to prolong infusions over usual dosing intervals or to administer total daily doses as a continuous infusion. However, it should be noted that these are not the only ways to increase fT > MIC. The simplest (and cheapest) technique is simply to reduce the time between doses. This technique not only eliminates the potential need for smart pumps and advanced laboratory monitoring for drug levels, but can still reduce total daily doses as with prolonged infusions despite more frequent dosing. Perhaps the most studied example is that of standard infusions of meropenem 1,000 mg every 8 hours compared to 500 mg infused every 6 hours. Despite a total daily dose reduction of 1,000 mg, several studies have shown similar success when doses are administered as 30 minute boluses. Patel, et al. set out to describe any possible differences in the outcomes and meropenem utilization between these two dosing strategies in a retrospective analysis of patients in a single community hospital. Meropenem 500 mg every six hours resulted in similar a mortality rate, length of stay, and duration of antibiotic therapy compared to traditional dosing of 1,000 mg every eight hours. These patients all received similar concomitant antibiotics and had similar baseline characteristics including degrees of renal dysfunction and sites of infection. In a multivariate regression of variables related to poor outcomes, the low-dose short-interval regimen was not associated.5 One of the primary points of contention with prolonged and continuous infusions of beta-lactams is the relatively poorly understood effect that renal dysfunction has on clinical targets for success. This issue may potentially be addressed by utilizing a low-dose shorter interval strategy. Ulldemolins, et al. conducted perhaps the most thorough analysis comparing different meropenem dosing strategies in critically ill septic patients undergoing continuous renal replacement therapy (CRRT) with various degrees of preserved urine output. Previously, most recommendations for meropenem doses during CRRT were 500-1,000 mg every eight to twelve hours, an unsatisfyingly wide dosing range. In this study, Monte Carlo simulations were done for 1,000 subjects using six different dosing regimens (three bolus and three extended infusion) across three categories of preserved urine output. Meropenem 500 mg every six hours infused over 30 minutes, whether anuric or at any level of native diuresis, was found to be just as capable at achieving 100% fT > MIC as 1,000 mg every eight hours infused over three hours for pathogens with an MIC of 2-4 mg/L.6 Furthermore, recent studies showing similar beta-lactam concentration-time profiles for IV push (≤5 minutes) and 30 minute infusions warrant consideration in order to avoid the need for IV pumps and small volume IV bags for beta-lactam administration. A recent study in the American Journal of Health System Pharmacy compared the kinetics of IV push and 30 minute infusions of meropenem, cefepime, and aztreonam across several different doses and intervals. There were few differences in the probabilities of target attainment across a range of pathogen MICs for all three drugs, with cefepime showing the least variability. With recent emphasis on conserving IV fluids and antimicrobial drug shortages becoming increasingly common, IV push infusion strategies can still achieve appropriate therapeutic activity while enabling conservation of now precious resources.7 These studies suggest that the ease of implementation and observed effectiveness of short interval beta-lactam administration may provide an attractive alternative to more advanced prolonged infusion methods. This is particularly relevant to less complicated infections with commonly susceptible pathogens and in resource-limited settings.

Further Advantages to Prolonged Infusions

As mentioned previously, despite few individual studies conferring a mortality benefit, there does seem to be a clear signal towards improved survival in select patients receiving prolonged infusion beta-lactams. Mortality and other patient-centered outcomes should remain the chief consideration for implementing pharmacodynamically optimized infusions, but further advantages warrant mention. “Antimicrobial resistance” has been a buzzword that invokes a spectrum of responses from all clinicians, from violently apathetic to fire-and-brimstone persecution of every fluoroquinolone ordered for a UTI. Whatever priority antimicrobial resistance holds in your institution, it is at the very least a public health dilemma that is becoming all too common and more difficult to overcome. Ideally, when pathogens are resistant to first-line therapies (usually a beta-lactam for most indications) it is preferable to switch to another antimicrobial for which the pathogen is susceptible. Previously, this approach may not have had a significant influence on outcomes, but in this era of increasing resistance, we often find ourselves in a dilemma where there are no equally effective alternatives, or with increasing frequency, we are faced with a pathogen sensitivity report that would imply the letter “R” stands for “Really should get an ID consult.” These pan-resistant pathogens usually warrant antibiotics from bygone eras when all cars looked the same, or some black-magic dosing strategies from the infectious disease service. However, there is a third option to combat resistance, even for the Titans of multi-drug resistant organisms, carbapenem-resistant pathogens. Prolonged infusion beta-lactams with usual total daily doses are capable of attaining target %fT > MIC to overcome pathogens deemed resistant according to CLSI or EUCAST breakpoint recommendations. Roberts, et al. conducted a pharmacokinetic study of several meropenem dosing strategies in critically ill patients without underlying renal dysfunction. For a target of 40% fT > MIC, standard meropenem doses of 1,000 mg every eight hours infused over 3 minutes was only effective for pathogens with MIC ≤ 2 mg/L. In contrast, 2,000 mg every eight hours infused over four hours achieved the optimal pharmacodynamic target for >90% of simulations in pathogens with MIC ≤ 8 mg/L. If ever there were a formulation of meropenem stable at room temperature for at least 24 hours, Monte Carlo simulations found that a 6,000 mg continuous infusion over 24 hours yielded reliable attainment of optimal bactericidal indices for pathogens with MIC ≤ 16 mg/L!8 In concordance with the findings of the recent meta-analyses of prolonged infusion beta-lactams, these administration techniques have likely resulted in decreased mortality due to increased coverage of the microbial population with greater resistance than the dominant strain. This subpopulation of resistant pathogens would likely flourish in the absence of competition while bathing in suboptimal concentrations of beta-lactams used to eliminate dominant, more susceptible strains. However, it is still relatively uncertain the influence that the site of infection may have on the success of prolonged infusion strategies and there are still knowledge gaps when considering more advanced infectious disease topics such as mutant selection windows and selective pressure among native microbial populations. Despite that, prolonged infusion beta-lactams should garner special attention among institutions with increasing frequencies of resistant pathogens.

References

Vardakas KZ, Voulgaris GL, Maliaros A, Samonis G, Falagas ME. Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials. Lancet Infect Dis. 2017.
Merrem [package insert]. Wilmington, DE: AstraZenica; December 2016.
Patel PR, Cook SE. Stability of meropenem in intravenous solutions. Am J Health Syst Pharm. 1997;54(4):412-21.
Osthoff M, Siegemund M, Balestra G, Abdul-aziz MH, Roberts JA. Prolonged administration of β-lactam antibiotics - a comprehensive review and critical appraisal. Swiss Med Wkly. 2016;146:w14368.
Patel GW, Duquaine SM, Mckinnon PS. Clinical outcomes and cost minimization with an alternative dosing regimen for meropenem in a community hospital. Pharmacotherapy. 2007;27(12):1637-43.
Ulldemolins M, Soy D, Llaurado-serra M, et al. Meropenem population pharmacokinetics in critically ill patients with septic shock and continuous renal replacement therapy: influence of residual diuresis on dose requirements. Antimicrob Agents Chemother. 2015;59(9):5520-8.
Butterfield-cowper JM, Burgner K. Effects of i.v. push administration on β-lactam pharmacodynamics. Am J Health Syst Pharm. 2017;74(9):e170-e175.
Roberts JA, Kirkpatrick CM, Roberts MS, Robertson TA, Dalley AJ, Lipman J. Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother. 2009;64(1):142-50.

Extended antibiotic infusions could save…

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