In a financially driven quest for antibiotic stewardship, does intensive care hold the key?

KEYWORDS:

• Antibiotics
• antibiotic stewardship
• intensive care
• critical care
• national health service

One message has permeated acute medical specialties like no other in the last decade: sepsis kills and early intervention—in particular administration of appropriate antibiotics—saves lives. The work of the Surviving Sepsis Campaign, the Sepsis Trust, and related groups in the dissemination of this information is to be applauded; their efforts have undoubtedly improved clinical practice and prevented countless deaths. The need for early antibiotics in severe sepsis is not in question. But the potential implications of unchecked antimicrobial therapy, for both individual and population, must be recognized and addressed. In England, the bio-ethical basis for rationalizing antibiotic use has been compounded by financial pressure: new government targets threaten hospitals with loss of income if they fail to curtail the use of broad-spectrum antibiotics. In this editorial, we explore the implications of these new targets and discuss how intensive care units (ICU) may offer the greatest gain in the quest for antibiotic stewardship.

For the individual, antibiotics pose many risks including renal and hepatic toxicity, rash, allergic reaction, and Clostridium difficile infection. For the health-care system, antibiotics account for a significant proportion of the pharmaceutical budget [1]. Of greatest significance, however, is the population-wide risk of resistant microorganisms. The increasing use of broad-spectrum antibiotics correlates with the rise in bacterial resistance to previously effective antimicrobial agents. As a consequence, international bodies recommend the widespread implementation of antibiotic stewardship [2]. This process, in practical terms, means early identification or exclusion of bacterial infection, the avoidance or cessation of antibiotics in the absence of infection, and – when antibiotics are administered – the delivery of a short but effective course [3].

The United Kingdom has a track record of using top-down interventions to improve patient outcomes and modify clinician behavior. Highly publicized methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile outbreaks in the late 1990s and early 2000s prompted a strong organizational response from the British Government and National Health Service. Mandatory reporting, infection reduction targets, and the elevation of responsibility for infection control to the level of the executive board were enforced by legislation (Health Act 2006; Health and Social Care Act 2008). In the years that followed, the incidence of MRSA bacteremia and Clostridium difficile fell by 85% and 53%, respectively [4]. Whilst a clear causative relationship can never be firmly established, it is on the background of this perceived success that the United Kingdom has approached the issue of antibiotic resistance and stewardship.

The Commissioning for Quality and Innovation (CQUIN) framework is an initiative intended to ‘deliver clinical quality improvements and drive transformational change’ [5]. The venture operates by offering financial incentive for the attainment of specific quality targets (known as CQUINs): a proportion of funding for a given health-care provider is dependent upon the attainment of these targets. Every year, a number of both national and local CQUINs are agreed upon. One of four national CQUINs for the year 2016/17 relates to antibiotic stewardship [5]. This promotes reduction in antibiotic use (as measured by defined daily dose) across secondary care organizations with particular focus upon carbapenems and piperacillin-tazobactam. All health-care providers—regardless of case mix and existing resistance patterns—are asked to achieve a 1% reduction in total antibiotic use and a 1% reduction in the utilization of carbapenems and piperacillin-tazobactam; there is an added requirement to review all antibiotic prescriptions within 72 h and that historical antibiotic consumption data will be provided. For a large, acute health-care provider such as ours, attainment of these targets is worth nearly £1 million in a year; the incentive to implement antibiotic stewardship is large.

Certain aspects of this target are problematic. Firstly, the 1% reduction is arbitrary and does not take into account appropriateness of antibiotic prescription. Secondly, the prescribing baseline against which UK hospitals are compared is the financial year 2013–14. Antibiotic use has been rising year upon year: between 2013 and 2014 alone it increased by 2.4% [6]. When the annual increase in antibiotic prescribing is considered, a reduction in 2016 prescribing to 1% below 2013/14 levels is, in real terms, a cut of more than a 5%. Thirdly, in previous centrally driven infection control initiatives, attainment of targets by individual hospitals was followed by more ambitious aims in subsequent years. It is not inconceivable that a similar approach will be adopted in enforcement of antibiotic surveillance. Those hospitals achieving the 1% reduction in antibiotic usage may then be faced with more ambitious targets, and in time be taken to the point that no further reduction is possible, and as such incur significant and unavoidable financial penalties. Finally, implementation of effective antibiotic stewardship is resource intensive and expensive [7]. In times of austerity, the cost of dedicating specialist pharmacist time to the attainment of antibiotic-related CQUIN targets may exceed the capabilities of some organizations. As a consequence, hospitals in the greatest financial difficulty may find themselves unable to deploy sufficient resources to achieve targets, further compounding monetary problems.

These difficulties in implementation should not distract from the importance of the venture. The national approach is to be lauded. However, individual health-care organizations, to whom the responsibility for execution falls, will require to utilize all resources in the pursuit of a sustainable antibiotic stewardship strategy. The ICU may, in this respect, offer significant opportunity.

1. The role of the ICU

ICUs manage only a small proportion of hospitalized patients but administer a disproportionately large quantity of antimicrobials [8]; this is particularly true for the broad-spectrum antibiotics implicated in resistance [8]. Antibiotic stewardship within the ICU is perceived as challenging for several reasons. Firstly, the severity of illness of the population creates a degree of nervousness amongst clinicians in the postponement or cessation of antibiotics [3]. Secondly, colonization is common, and it may be difficult to determine the pathogenicity of microbiological isolates [9]. Finally, the unique and complex physiology encountered in critical illness renders pharmacokinetic models unreliable with potential for underdosing or overdosing of antibiotics; the efficacy of standard regimens may thus vary between patients [10].

Yet the ICU also has major advantages in the quest for antibiotic stewardship. The highly monitored and closely supervised environment offers the opportunity to optimize antibiotic delivery, track effect, and make early decisions regarding escalation or cessation of therapy.

2. Optimization of antimicrobial therapy

Efficacy of antimicrobial therapy is dependent upon achieving sufficient plasma and target tissue concentrations. The standard dosing regimens, aimed at achieving optimal pharmacokinetics, are typically developed in animal models and in the critically ill human, may not be accurate. Fluid shifts and extracorporeal circuits alter the volume of distribution; hypoalbuminemia and abnormal plasma pH affect protein binding and fraction of available drug; altered renal function and the use of renal replacement therapy impact upon drug clearance. Failure to consistently achieve therapeutic plasma levels is detrimental on two fronts: infection is not adequately treated, necessitating prolongation of the antibiotic course; under-dosing potentially selects out resistant strains.

Variability in kinetics may be, to some extent, predictable. Adjustment of dose in response to accurate measurement of weight, body surface area, creatinine clearance, and albumin are feasible, particularly in the ICU. Regular measurement of plasma antibiotic levels provides guidance and reassurance regarding the efficacy and safety of the course. Typically, only aminoglycoside and glycopeptide levels are readily available, this practice reflecting the narrow therapeutic range of these agents. Therapeutic monitoring of other agents, such as beta-lactams, is feasible; however, the utility of such monitoring in agents with wide therapeutic effect is questionable [11].

Mode of delivery may be important. For beta-lactams, in whom time above minimum inhibitory concentration is the primary determinant of efficacy, delivery by means of continuous infusion rather than intermittent bolus has been shown to produce a more favorable pharmacokinetic profile, although the impact of this upon clinical outcomes is unclear [12].

It has also been suggested that combination antibiotics optimize therapy and thus allows reduction in antibiotic duration. Dual agents may provide broader cover, offer a synergistic effect, or have an immunomodulatory role [10]. Meta-analysis [13] of this approach has yet to show any increase in clinical efficacy or outcome improvement; the potential increased risk of combination antibiotic therapy to patient and population must also be considered.

3. Assessment of antimicrobial effect

The continuous physiological monitoring and regular blood sampling in ICU offers the opportunity to observe the response to antibiotics. As such, antibiotic courses can be tailored to individual need and response. Failure of the inflammatory response to settle should prompt consideration of a non-infective cause for inflammation, reevaluation of the need for (further) source control, or change of antimicrobial agent; significant improvement allows early cessation of the antibiotic course.

The majority of patients on the ICU exhibit an inflammatory state. The challenge is to differentiate inflammation of bacterial sepsis from other etiologies. Commonly used markers of infection and inflammation—temperature, white cell count, c-reactive protein (CRP)—have low specificity for bacterial infection. Procalcitonin (PCT) is reported to have greater specificity for bacterial sepsis, and has less time lag than CRP [14]. PCT, measured on initial suspicion of sepsis, is reported to identify bacterial infection with an area under the receiver operating characteristics (AUROC) curve of 0.78; CRP by contrast exhibits an AUROC of 0.71 [14]. A low PCT therefore offers some reassurance that antibiotics can be delayed pending microbiological results; an elevated PCT is more difficult to interpret as it can be associated with other inflammatory states, in particular major trauma. For the patient receiving antibiotics, the trend in PCT can guide duration. Systematic review has demonstrated reduced antibiotic exposure [15].

4. Summary

Antibiotics save lives and, in the septic patient with end organ dysfunction, should be administered without delay. The consequences of unchecked antibiotic therapy must not, however, be ignored and the antibiotic exposure of patient and population limited to the minimum necessary. In England at least, the incentive for antibiotic stewardship is no longer solely bio-ethical; financial pressures have been brought to bear. In this antibiotic stewardship challenge, we believe that it is for intensive care—with its high use of broad-spectrum antibiotics but unique ability to safely modify antibiotic use—to lead the way.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.