Antibiotic usage and increasing antimicrobial resistance (AMR) mount significant challenges to patient safety and management of the critically ill on intensive care units (ICU). Antibiotic stewardship programmes (ASPs) aim to optimise appropriate antibiotic treatment whilst minimising antibiotic resistance. Different models of ASP in intensive care setting, include “standard” control of antibiotic prescribing such as “de-escalation strategies”through to interventional approaches utilising biomarker-guided antibiotic prescribing. A systematic review of outcomes related studies for ASPs in an ICU setting was conducted. Forty three studies were identified from MEDLINE between 1996 and 2014. Of 34 non-protocolised studies, [1 randomised control trial (RCT), 22 observational and 11 case series], 29 (85%) were positive with respect to one or more outcome: These were the key outcome of reduced antibiotic use, or ICU length of stay, antibiotic resistance, or prescribing cost burden. Limitations of non-standard antibiotic initiation triggers, patient and antibiotic selection bias or baseline demographic variance were identified. All 9 protocolised studies were RCTs, of which 8 were procalcitonin (PCT) guided antibiotic stop/start interventions. Five studies addressed antibiotic escalation, 3 de-escalation and 1 addressed both. Six studies reported positive outcomes for reduced antibiotic use, ICU length of stay or antibiotic resistance. PCT based ASPs are effective as antibiotic-stop (de-escalation) triggers, but not as an escalation trigger alone. PCT has also been effective in reducing antibiotic usage without worsening morbidity or mortality in ventilator associated pulmonary infection. No study has demonstrated survival benefit of ASP. Ongoing challenges to infectious disease management, reported by the World Health Organisation global report 2014, are high AMR to newer antibiotics, and regional knowledge gaps in AMR surveillance. Improved AMR surveillance data, identifying core aspects of successful ASPs that are transferable, and further well-conducted trials will be necessary if ASPs are to be an effective platform for delivering desired patient outcomes and safety through best antibiotic policy.

The intensive care unit (ICU) is often regarded as an epicentre of infections, with sepsis being the second non-cardiac cause of mortality[1]. In two major cross-sectional studies of sepsis in the intensive care setting, Sepsis in European Intensive care units (EPICII)[2] and SOAP[3], 50% and 38% of all patients respectively had infections.

Mortality from Sepsis in the critically ill can approach 50%, with time to initiation of antibiotic treatment as the single strongest predictor of outcome. Each hour’s delay increases mortality by 7.6%, over the first 6 h[4]. ICUs account for 5%-15% of total hospital beds but 10%-25% of total healthcare costs[5]. Sepsis increases patient-related costs six-fold[6]. In the United States, antibiotic-resistant infections are associated with 23000 deaths and 2 million illnesses per year, with estimated excess direct healthcare costs of $20 billion and $35 billion in lost productivity[7]. Resistant organisms can increase patient-related prescribing costs by $8000 to $30000[1]. Such empiric practice, deemed necessary at the point of care, due to uncertainty of causative organisms, is often ineffective and results in higher costs.

Antimicrobial resistance (AMR) is an increasing global healthcare phenomenon, with apocalyptic predictions of a post-antibiotic era where common infections and minor injuries may not be treatable by conventional antibiotics[8]. A WHO global report describes the majority of world regions with over 50% resistance of Escherichia coli (E. Coli) and Klebsiella Pneumoniae to 3^rd generation cephalosporins and fluoroquinolones. The increasing prevalence of carbapenem-resistant organisms, and other multi-resistant strains such as Methicillin resistant Staphylococcus aureus (MRSA) as well as extended-spectrum beta-lactamase (ESBL) producers justifies these concerns. Specifically, AMR has a number of proposed causes. Data from United States National Nosocomial Infection Surveillance programme (NNIS) demonstrated 20%-30% increase in resistant isolates of Pseudomonas, Staphylococcus aureus and Enterococcus across a 5-year period[9]. In particular, fluoroquinolone-resistant Pseudomonas showed more than 50% increase during the period.

Intensive care units represent the heaviest antibiotic burden within hospitals. They are described albeit provocatively, as a factory creating, disseminating and amplifying antibiotic resistance[1]. In a European multi-centre cross-sectional prevalence study of academic ICUs, there were 14% of Klebsiella ESBL-producers, and nearly 25% of Pseudomonas aeruginosa isolates were carbapenem-resistant[10].

ICUs in emerging economies report notably higher prevalence of ESBL-producers[11-13] and carbapenem-resistant organisms[11-14]. Of note, the majority of multi-resistant Acinetobacter (MRA) isolates in these studies also demonstrates reduced susceptibility towards carbapenems[11-13].

The dynamics of antibiotic resistance are multifarious. Firstly, antibiotic usage in the animal and plant industry, to improve growth and productivity, is a major contributor to AMR[15]. The increasing prevalence of ESBL producers in animal products has been suggested. Furthermore, a link between antibiotic resistance in human clinical microbiological isolates and those from poultry has been raised[16]. On the contrary, other studies rule out such associations between chicken meat and colonisation of ESBL-producing E. coli in humans[17].

Within the ICU setting itself, causes of AMR may conveniently be categorised by procedure-related, management-related, and antibiotic-related factors. Procedure-related factors include central venous catheters[18,19] and endotracheal intubation for mechanical ventilation[20]. Management-related factors include poor adherence to infection control policy[20], lack of microbiological surveillance with delayed/failed recognition of resistant isolates[21], patient overcrowding[22,23], understaffing and implicit spread of AMR through human vectors[24,25], prolonged ICU length of stay[20,26], and pre-infection with resistant organisms at the time of ICU admission[26]. Antibiotic-related factors are related to the appropriateness and duration of treatment. Non-controlled usage[27] is well documented. Ceftriaxone for example, was shown to cause a rise in rates of vancomycin resistant Enterococci (VRE) rates[28]. The use of broad-spectrum antibiotics, often as the first step in therapy for patients with suspected infections, has accumulated considerable evidence regarding its association with the development of antibiotic resistance[20,26,29-32]. Similarly, the ease of access to certain antibiotic classes, either through their availability over-the-counter in certain countries (i.e., penicillins, fluoroquinolones) or through unfounded clinician concerns of missing unlikely bacterial infection, leads to documented AMR, although causation proves difficult at an individual patient level. As such, the evidence behind the duration of treatment and AMR is comparatively lacking. In the PneumA trial, patients with ventilator-associated pneumonia (VAP), who had prolonged antibiotic treatment (15 d vs 8 d) developed higher rates of multi-resistant Pseudomonas isolates[33]. Clearly, one must be circumspect about distinguishing natural selection of antibiotic resistant bacteria through necessary antibiotic usage and judgements of inappropriate antibiotic usage as causation of AMR.

Although only shown in hospital wards rather than ICU, failure to de-escalate or discontinue therapy[34,35] is also a likely contributory factor to antibiotic resistance in ICU.

The exact impact of multidrug resistance (MDR) microbial organisms is difficult to quantify, depend as it does on, the causative microbe and its pathogenicity, patient populations, severity of illness and the appropriateness of therapy[36]. The association of increased ICU mortality and hospital length of stay (LOS) with MRSA, VRE, Acinetobacter, Pseudomonas and Klebsiella are well documented[37]. These mirror poor outcomes associated with such organisms in general ward settings[38]. From a financial perspective for instance, bloodstream infections caused by MDR organisms are estimated to increase treatment costs by 50%[39]. What effect such local outbreaks of MDR bacteria have on process of care within a hospital setting and outwith is dependent on effective surveillance, and links between infection control, Public health, and health policy makers. This data is all too often insufficient or not translated into effective intervention.

Antibiotic stewardship programmes (ASP) are regarded as a keystone in tackling AMR in ICU. The intention is to reduce antibiotic resistance by minimising selection pressure, through optimising antibiotic therapy[40-44]. In Europe, the implementation of ASP follows a “top-down” model, with European council recommendations (i.e., the Prague framework) and national-level guidance (e.g., The Scottish Management of Antimicrobial Resistance Action Plan, ScotMARAP) informing delivery programmes at critical care network and individual unit levels[45,46]. In the context of these strategic initiatives, we have conducted the following systematic review of published ASPs in the ICU.

Antibiotic usage and resistance represent an increasing global concern. The latest figures from the United Kingdom reveal that hospital-acquired infection costs GBP 1 billion annually[99], and USD 4.5 to 5.7 billions in the United States[100]. It is unsurprising that commentaries refer to “crisis” and “catastrophe” when describing possible worst case scenarios of uncontrolled AMR. The wording from the 2014 WHO global report of such a post-antibiotic era emphasises the need for action to prevent such a time. To tackle this increasing challenge, one might envisage a combined approach involving the development of next generation antibiotics (significant development times and costs), new innovations such as nanotechnology in infection control[101], together with strategies to optimise the effective use of currently available antimicrobials. Thus, ASPs involve a delicate interplay between economy, health and clinical evidence. To date the current high level evidence base for ASPs remains limited, with most of the reported studies being observational in nature. Those protocol based RCTs targeting de-escalation of antibiotics have demonstrated reduced usage, and on occasion reduced resistance patterns, length of stay but not manifested as survival benefit. Clinical decision support tools are of increasing interest in this regard.

Strategies to minimise antibiotic usage are multifaceted. It remains uncertain whether the reported success in literature with regard to ASPs could be attributed to ASP alone, or confounders such as concurrent infection control policies. Should an ASP not by implication require an effective infection control policy? What would be the added value of the ASP? And what components should the ASP adopt? The role and impact of bed occupancy, staffing ratios and infection prevalence on antibiotic stewardship outcomes clearly require incorporation into study design. Further randomised controlled trials or indeed cluster studies, with staggered implementation of ASPs, where effective infection control policies are already in place may be required. Careful study design with appropriate components of the ASP, that could be implemented widely, would be desirable.

The dynamics of antibiotic resistance following the implementation of ASPs has been described as “balloon squeezing effect”[102]. It is believed that the development of antibiotic resistance towards one class of antibiotics, could lead to the emergence of resistance against another class, rendering multi drug resistance. The molecular mechanisms behind this concept remain unclear. However, the use of quinolones for Pseudomonas aeruginosa may be relevant. Quinolones selectively upregulate the bacterial membrane efflux system MexEF-OprN, and the loss of co-regulated porin OprD results in carbapenem resistance[103]. In a hypothetical situation where quinolones are routinely introduced empirically in favour of “targeted antibiotics” in a given ASP antibiotic regimen, resistance to both quinolones and carbapenems may develop.

Uncertainties around AMR in ICU being due to antibiotic selection pressure and distinguishing pathogenicity versus bystander effect of resistant organisms will remain a challenge for implementing fixed antibiotic protocols as part of ASPs. The lack of wholescale uptake of selective decontamination of the gut (SDD) or selective oral decontamination (SOD) to reduce rates of sepsis, is an example of this challenge[104,105]. Despite high level evidence for their efficacy, uptake is poor[106,107], with concerns regarding emergence of resistance being borne out in some settings[108].

Further evidence of practical difficulties in implementation of ASPs is the recent RCT of a PCT-based ASP. This was terminated prematurely due to poor clinician adherence to the algorithm[98]. Understanding the rationale behind clinician compliance and lack of it, specific to ASP antibiotic start and stop decisions will be important in designing future studies.

The culture positivity of microbiological isolates among ICU patients with suspected infections is generally low. EPIC II and SOAP studies reported culture positivity in only 51.4% and 60% of patients[2,3]. Furthermore, time required to identify the causative organism far exceed the clinical decision time. Until such time as rapid diagnostics can confidently rule out suspected infection within minutes, and the knowledge that delayed or inappropriate antimicrobials in sepsis equates with higher mortality, even PCT-guided ASPs might not prevent clinician decision tree analysis based upon opinion. Thus, studies investigating its role in treatment escalation yielded relative limited information to this date. The prospect of novel rapid identification tools to enhance ASP programmes is another crucial facet of ASP[47]. The call here has been heeded, with the announcement of monetary prizes of up to $17 million, and $20 million from the NESTA foundation (a Uinted Kingdom organisation through the Longitude prize 2014), and the United States NIH/Biomedical Advanced Research Authority[7,109,110]. The US Administration also released its National Strategy on Combating Antibiotic-Resistant Bacteria. In addition, the President’s Council of Advisors on Science and Technology (PCAST) is releasing a related report on Combating Antibiotic Resistance. The National Strategy provides a five-year plan for enhancing domestic and international capacity to prevent and contain outbreaks of antibiotic-resistant infections; maintain the efficacy of current and new antibiotics; and develop and deploy next-generation diagnostics, antibiotics, vaccines, and other therapeutics. The PCAST report provides recommendations from the President’s Council and allied scientific and professional agencies,to act for the development of more effective ASPs[7].

The costs associated with ASP, have so far been limited to those of the prescribed antibiotics. Nonetheless, costs related to staff employment and education, as well as management and information technology, will require necessary health economic analysis.

It is said that, where ASP is today, is infection control programmes thirty years ago[111]. Thus the unanswered questions we encounter today might well hide the solution to the increasing burden of infection and AMR in ICUs and beyond. A multifaceted approach involving key stakeholders - healthcare, industry, technology, economy, security, government, charity and the public is warranted, to overcome AMR and perpetuate the future utility of antibiotics[112]. Refined and tailored Antibiotic stewardship programmes in (and outwith) ICU will be an important part of that partnership.