Review on strategies to minimize the appearance of multi-drug resistant organism

Background: The use of antibiotic drugs (ABX) in hospitals, and especially in intensive care units (ICU), is widespread. The early administration of ABX therapy can improve survival rates. The influence and impact of the ABX are observed in the patients who receive them (clinical response, course) and in the ecosystem surrounding the patient (hospital flora). Aim of the review: The objective of this review is to identify strategies that reduce or limit the appearance and transmission of multidrug - resistant microorganisms. This identification can then develop a rational use of the ABX plan in the ICU. Method: The following databases were queried;


Introduction
The use of antibiotic drugs (ABX) in hospitals, and especially in intensive care units (ICU), is widespread.The early administration of ABX therapy can improve survival rates (Mok et al., 2014).The influence and impact of the ABX are observed in the patients who receive them (clinical response, course) and in the ecosystem surrounding the patient (hospital flora).This impact is especially visible in the critically ill patients in the endemic flora of the ICU (Alvarez Lerma et al., 2010).
Treatment with broad-spectrum ABX is generally used for early treatment, since it has been shown that preemptive treatment, with the appropriate ABX, reduced mortality rates.This approach may expose individuals to excessive use of ABX and therefore, the selection of resistance to these pathogens (Silva et al., 2013).The European Centre for Disease Prevention and Control (ECDC) and the European Medicines Agency (EMA) estimated that each year 25,000 Europeans die as a direct consequence of a multidrugresistant infection (ECDC/EMA, 2009).
In Spain, as some projects in other European Member States (e.g. the Netherlands (Schuts et al., 2016)), the National Action Plan on Antimicrobial Resistance (AEMPS, 2018) was nationally coordinated in 2014 by the Spanish Agency of Medicines and Medical Devices, together with six Ministries, with the objective of minimizing the impact of antimicrobial resistance and how to be addressed jointly from the human and veterinary health.The importance of the ABX as part of the pharmacotherapy arsenal is unquestionable, hence the importance of improving the management of the knowledge about them.
Health and social care practitioners have to make clinical decisions daily.Compatible update of knowledge and health care is a complicated task, and Clinical Practice Guidelines (CPG) are useful tools to facilitate decision-making.Initiatives such as the Program for Optimizing the use of Antimicrobials (PROA) in Spanish hospitals (Rodriguez-Bano et al., 2012) can contribute to improve policy of ABX, and minimize the emergence of resistance in microorganisms.Within the framework of the ICU it emphasizes the "Zero resistance" programme (Garnacho Montero et al., 2015).
One of the lines of work, typically proposals from hospital pharmacy services, is the sequential therapy, but there are interventions whose evidence is not proven and that should be evaluated.These include the therapeutic de-escalation, and cycling of ABX and preemptive treatment.The objective of this review is to identify strategies that reduce or limit the appearance and cross transmission of multidrug-resistant organisms in order to make rational use of the ABX.

Data and Methods:
Strategies to minimize the emergence of multidrug-resistant organisms in ICU with policy measures of ABX that address: A)

A) De-escalation therapy
Of 98 identified studies, we have analyzed 3 studies that met the criteria of inclusion: 1 SR (Silva et al., 2013), 1 RCT (Kim et al., 2012), and 1 CPG (Dellinger et al., 2013).The SR, despite identifying several studies, discards them for being uninteresting interventions or clinical conditions not relevant to the review.
The study done by Kim et al., 2012 shows statistically significant differences in favour of de-escalation in terms of the adequacy of the ABX and against the de-escalation in the time of occurrence of multi-drug resistant organism, primarily due to MRSA; HR = 3.84 (95% CI: 1.06; 13.9).Mortality, duration of the ABX, stay in ICU or adverse treatment, showed no statistically significant differences.Dellinger et al., 2013 were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence, and include in the international CPG: 1) the need to identify pathogens and apply more efficient ABX treatment, 2) reduction of the spectrum of antibiotic coverage, and 3) the reduction of the duration of the ABX treatment.

This
decreases the chances that the patient develops infections by multi-resistant pathogens and the beginning of a pattern of broad-spectrum Volume 2 Issue 3, July 2018 treatment ABX to increase the effectiveness of the treatment and improve health outcomes.
B) Cycling of ABX Two studies were selected (Nijssen et al., 2010;Martinez et al., 2006) that compare ABX cycling to other interventions.The first, a period of cycling's three months, gets 14 crops with Enterobacteriaceae resistant to third generation cephalosporin's (3GCRE) for every 1,000 patients per day to risk.This data is the same as during the baseline period, observation of the ICU.During the three months of not cycling (reducing exposure to beta-lactams and introduction of fluoroquinolones), there are 18 crops with (CPG) for every 1,000 patients per day to risk.During the three months of cycling, isolated 2.5 (CPG) resistant to fluoroquinolones (FRE) for every 1,000 patients per day to risk, being the similar results of the baseline period (2.1 FRE 1,000 patients day to risk) in contrast with the period of not cycling, which they have 8.3 FRE for every 1,000 patients per day at risk (Nijssen et al., 2010).
When the explanatory model is adjusted by type of ICU, age of the patient, gravity -APACHE II, indication of admission, and reason of contacts, not cycling for 3 months in ICU (reduction of beta-lactam and introduction of fluoroquinolones), increases the speed of appearance of FRE in 4.1 times with regard to the cycling of ABX (adjusted HR = 4.1 [95% CI: 1.4; 11.9]) (Nijssen et al., 2010).The Group of Martinez et al. (2006) analyzed along 8 months, in two ICU, a pattern of cycling of ABX with another mixed pattern that was administered to patients, as they enter consecutively to analyze the emergence of resistance in gram-negative enteric Bacilli.
They found that the prevalence of resistance acquired during two periods of study was highest during the mixed period than during the period of cycling (9% vs. 3% respectively, p = 0.01) for Pseudomonas aeruginosa and specifically, for cefepime.No statistically significant differences for other bacilli can be seen on Enterobacteriaceae (Martinez et al., 2006).

C) Preemptive treatment
No studies have been found with robust enough methodological designs that address the preemptive treatment.Study designs were not enable to provide robust evidence about preemptive treatment (De Waele et al., 2003;Piarroux et al., 2004).

Cross transmission
We found 5 studies, of which 3 are SR (Lam et al., 2012;Pammi et al., 2011;Backman et al., 2008) and 2 RCT (Huang et al., 2013;Climo et al., 2013).A SR evaluates the effectiveness of the measures of oral hygiene in reducing colonization of Staphylococcus aureus (Lam et al., 2012) and given that only 3 of the 15 studies included in the review had been done with ICU patients with mechanical ventilation (MV), results of the three studies were displayed (Pedreira et al. 2009;Scannapieco et al., 2009;Fourrier et al., 2000) with broader objectives.
In all three studies, part of the intervention consists of performing oral hygiene with chlorhexidine in critically ill patients with MV. Results from the Paediatric ICU show no difference on colonization of oropharyngeal, duration of the MV, length of stay in ICU, or isolation of multidrug-resistant bacteria (Pedreira et al. 2009).A second study with adult patients showed a significant reduction in the number of isolates by culture Staphylococcus aureus versus placebo at 2 and 4 days of admission to ICU with MV.There was no statistically significant difference in the occurrence of pneumonia, or it has been observed that interventions at the time delayed the onset of pneumonia Volume 2, Issue 3, July 2018 (Scannapieco et al., 2009).
The work done in France excludes study to toothless patients and select patients with exclusively medical processes all with MV.Oral isotonic serum bicarbonate and oropharyngeal suction cleaning 4 times a day improve in a statistically significant way to more nosocomial infection (NI) that the application of gel with chlorhexidine associated with 0.2% in teeth and gums with sterile glove 3 times daily (p = 0.018).The application of chlorhexidine is also associated with a reduction in the number of ventilation-associated pneumonia (VAP) (p < 0.05) (Fourrier et al., 2000).
The SR of Pammi et al. 2011 sought to analyze the effect of isolation measures in reducing the cross transmission of Candida from infants colonized or infected.No evidence was found supporting or not of isolation measures, both individually and in group, in ICU of infants (Pammi et al., 2011).
A SR identified which aims to evaluate the relationship between hand hygiene interventions and the incidence of NI (Backman et al., 2008).In addition to 35 studies, one included is a RCT in Paediatric ICU selected (except kidney) solid organ transplant patients.Observed hand washing with chlorhexidine before and after each patient contact or the use of robe and latex gloves non sterile with each patient contact, reduce the incidence of NI ICU in a statistically significant way between the previous year and the 6 months after the interventions (4.9/100 days vs. 2.2/100); p = 0.0004.Statistically significant differences were not found in NI average in transplanted between groups (Slota et al., 2001 p = 0.01), as well as bacteraemia caused by others pathogens acquired in ICU (p <; 0.001).Statistically significant differences for bacteraemia by MRSA acquired in ICU are not observed both to compare between periods and between groups.Comparing between groups, universal decolonization was the intervention that reduced the occurrence of positive cultures for MRSA and ICUacquired bacteraemia by other pathogens more effectively (Huang et al., 2013).
A multicenter RCT, with the participation of 9 ICU (a total of 7,727 patients) assessed the utility of body hygiene through cleaning wipes, with chlorhexidine gluconate 2%, to reduce the risk of acquiring multiresistant organisms and bacteraemia nosocomial in critically ill patients.The duration of the intervention period decreased, in a statistically significant way, a 23% NI MRSA and Vancomycin-resistant Enterococcus (VRE), a 28% nosocomial bacteraemia, 31% primary bacteraemia, and 53% bacteraemia, associated to central venous catheter.A reduction of 90% of fungaemia is also described, associated with central venous catheter (Climo et al., 2013)

Discussion
Studies of quality capable of sustaining analyzed ABX policy measures have been searched and identified.It would be necessary to design prospective research studies that can establish a causal relationship between the policy measures of ABX and the emergence of multidrug-resistant organisms in ICUs reduction.Studies with more robust designs that allow you to determine if oral hygiene in critically ill patients with MV's more 48 hours has a clinically relevant impact is required.As antimicrobial stewardship Pharmacist, you can make prospective audit and feedback, if you review the information and recommend that the prescribing team narrow therapy.
Antibiotics should be discontinued within 48 hours after surgery.It is necessary to carry out studies that allow determining the clinical impact of the role of isolation measures in patients, colonized or infected by Candida.There is no doubt of the importance of interventions to improve hand hygiene to reduce the incidence of NI in critically ill patients.Universal decolonization in critically ill patients reduce bacteraemia, prevents the realization of surveillance test, reduces the number of isolates of contact, and decreases the chances of transmission of infection to other patients.The personal hygiene of critically ill patients with chlorhexidine-impregnated wipes reduces the transmission of bacteria resistant to other patients.Blood cultures will be negative in most patients, despite a bacterial of fungal origin of sepsis.Clinical judgment is needed when considering discontinuation of antimicrobials.According to the results of the microbiological studies, a treatment with a more adjusted antimicrobial spectrum by one of the following two pathways: 1) change of ABX, and; 2) Interrupt an antibiotic combination.An additional strategy to shorten the duration of ABX treatment (Alvarez Lerma et al., 2010;Silva et al., 2013).Crop performance is a prerequisite for the use of antibiotic de-escalation in critically ill patients, although the decision to reduce the intensity of treatment should be based on the patient's clinical course (Silva et al., 2013).Therapeutic de-escalation aims to achieve adequate antibiotic coverage through the use of ABX in a targeted manner, reducing the spectrum of empirical coverage and reducing selective pressure on the patient's flora as well as the ecosystem in which the latter remains.
The cycling of ABX consists of the determined alternation of ABX by which the use of an ABX or specific ABX class is restricted for a certain period of time to be reintroduced subsequently (Sandiumenge et al., 2003).Other authors describe cycling as the periodic substitution of one class of ABX by another class or the combination of ABX that present a spectrum of similar activity, but do not share the same mechanism of resistance (Alvarez Lerma et al., 2010).It is intended to minimize the occurrence of bacterial resistance to the ABX in use, reducing the selective pressure exerted on the microbial flora (Sandiumenge et al., 2003).
Preemptive treatment is the administration of ABX in some patients before clinical signs of infection appear.The application of this concept to critically ill patients is based on the identification of patients at risk of infections associated with high mortality, such as systemic fungal infections (Alvarez Lerma et al., 2010).
Having information on the quality of antibiotic prescription can help identify problems and implement strategies to improve this prescription; the European Surveillance of Antimicrobial Consumption (ESAC) has developed a group of indicators of antibiotic use in outpatients with the objective to measure the quality of the use of antibiotics and thus improve their use (Coenen et al., 2007).

Conclusion
Despite the fact that no prospective studies were identified in this SR, rationale and day-to-day clinical practice experience suggest that multidisciplinary participation of different specialists in ABX's Infection and Policy Commission (or the ABX Commission), or the Pharmacy and Therapeutics Committee, might improve the development and application of these strategies.

Table 1 . Summary of recommendations for preventing ventilator-associated pneumonia (VAP) in adult patients -Society for Healthcare Epidemiology of America/Infectious Diseases Society of America (SHEA/IDSA)
* There are very little data on head-of-bed elevation, but it is classified as a basic practice because of its simplicity, ubiquity, low cost, and potential benefit.¶ There are abundant data on the benefits of digestive decontamination but insufficient data on the long-term impact of this strategy on antimicrobial resistance rates.Δ May be indicated for reasons other than VAP prevention.