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Keywords:

  • Antibiotic management;
  • resistance;
  • selection pressure

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Global management strategy
  5. Antibiotic selection
  6. Limitation of antibiotic use: i) Monotherapy
  7. ii) Duration
  8. iii) De-escalation and discontinuation
  9. iv) Restriction and rotation
  10. Reduction in infection
  11. Conclusion
  12. References

Mortality from severe bacterial sepsis remains high. The pathogenesis involves production of pro and anti-inflammatory cytokines which mediate: neutrophil adhesion to the endothelium, diffuse capillary leak, disseminated intravascular coagulation, vasodilatation and mitochondrial dysfunction, all of which culminate in microcirculatory failure. Therapy is multifaceted. As described in ‘the surviving sepsis guidelines’, many therapeutic interventions, such as early goal-directed resuscitation, low dose intravenous steroids, strict glucose control, recombinant activated protein C and ventilation according to ARDS- net criteria are critical to survival. However appropriate empiric antibiotic therapy initiated early is pivotal. Empiric therapy should be designed with regard to the bacterial epidemiology within the unit and the aim should be to optimise outcome while yet attempting to reduce the potential for resistance development. Antibiotic therapy for resistant organisms consists of the carbapenems, including ertapenem for ESBL's, cefepime, piperacillin/tazobactam and, on occasion, the Gram-negative quinolones, ciprofloxacin and levofloxacin. Consideration should be given to the possibility of ‘collateral damage’, where overuse of an antibiotic predisposes to multi-drug resistance. Antibiotics should be limited, where possible, to those organisms that are pathogens and not colonisers and should be discontinued if sepsis is not confirmed or there is rapid resolution of clinical indicators of sepsis. De-escalation strategies should be consistently employed and the duration of therapy should be tailored to clinical response. Continuation beyond 8 days is generally detrimental in terms of the potential for superinfection with resistant organisms. Failure of response necessitates, initially, a re-evaluation of source control and obsessive culturing of likely sites of sepsis prior to random antibiotic changes.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Global management strategy
  5. Antibiotic selection
  6. Limitation of antibiotic use: i) Monotherapy
  7. ii) Duration
  8. iii) De-escalation and discontinuation
  9. iv) Restriction and rotation
  10. Reduction in infection
  11. Conclusion
  12. References

Severe sepsis results in a series of events that culminate in organ dysfunction and hypotension [1]. In the case of Gram-negative sepsis, the transcription factor, nuclear factor kappa B, is activated by endotoxin and, in the case of Gram-positive sepsis, by cell wall products such as lipotechoic acid and peptide exotoxins. Nuclear factor kappa B translocates to the nucleus, where it mediates the production of proinflammatory cytokines such as tumour necrosis factor, interleukin-1 and interleukin-6, which mediate adhesion of polymorphonuclear leukocytes to the endothelium, with consequent capillary leak, coagulation and vasodilatation. These systemic events and the organ dysfunction that ensues are associated with an unacceptably high mortality [2]. This is despite ongoing progress in the understanding of the pathogenesis of the condition. The incidence of severe sepsis has remained similarly high and actually appears to be increasing [3,4].

Global management strategy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Global management strategy
  5. Antibiotic selection
  6. Limitation of antibiotic use: i) Monotherapy
  7. ii) Duration
  8. iii) De-escalation and discontinuation
  9. iv) Restriction and rotation
  10. Reduction in infection
  11. Conclusion
  12. References

Strategies have been developed to meet this challenge in the form of the ‘Surviving Sepsis Guidelines’, which represent an international consensus on the best available standards for management of sepsis, regardless of its aetiology [5]. These guidelines concern the utilisation of therapeutic interventions that have been proven to reduce mortality or would be expected to do so. These interventions include adequate early resuscitation with appropriate fluid, inotropes or vasopressors, ventilation according to the ARDS-net criteria, utilisation of low-dose steroids in situations of relative cortisol deficiency, insulin infusion to maintain euglycaemia, early enteral nutrition and the administration of the anticoagulant and anti-inflammatory agent drotrecogin-α (activated protein C). In addition to the above, the utilisation of appropriate antibiotics, administered at an early stage of therapy, is recognised to be pivotal in ensuring a positive outcome.

Antibiotic selection

  1. Top of page
  2. Abstract
  3. Introduction
  4. Global management strategy
  5. Antibiotic selection
  6. Limitation of antibiotic use: i) Monotherapy
  7. ii) Duration
  8. iii) De-escalation and discontinuation
  9. iv) Restriction and rotation
  10. Reduction in infection
  11. Conclusion
  12. References

Antibiotic management has become particularly topical because of the realisation that inappropriate therapy is associated with higher mortality and that indiscriminate use of broad-spectrum antibiotics is driving the development of in-hospital resistance [6–8]. There are currently more than eight studies, only some of which are referenced in this paper, demonstrating that inappropriate initial therapy is associated with a significant increase in mortality, which is not reversed by changing the antibiotics once the sensitivity is known [9–12]. One of these studies demonstrated that in-hospital mortality was eight-fold greater for patients receiving inappropriate therapy within the first 24 h (relative risk 1.4 (1.11–1.80) log rank p = 0.0017 vs. those receiving appropriate therapy) [13]. The likelihood that therapy will be appropriate depends on the levels of resistance in the unit (for example, if resistance levels are low, inappropriate therapy would be unusual). Risk factors for resistance include having previously received antibiotics, duration of hospital stay (> 5 days), previous hospitalisation and mechanical ventilation [14–16].

As a consequence, although it would be preferable for treatment to be culture-driven, empirical therapy is usually necessary and should be designed to cover the pathogens most frequently encountered in each particular unit. Pathogens vary from unit to unit, from hospital to hospital and, temporally, within units themselves; and thus routine surveillance should be performed frequently and repetitively [12,17,18]. This may well mean that it is necessary to employ both Gram-positive and Gram-negative coverage. Empirical Gram-negative coverage, depending on unit sensitivities, includes one or more of the following: cefepime, imipenem, meropenem, piperacillin–tazobactam, ciprofloxacin/levofloxacin or ertapenem. Very few new effective ‘Gram-negative’ antibiotics are in the pipeline. Although tigecycline will soon be available and will be extremely useful against Acinetobacter, it has no efficacy against Pseudomonas[19]. Compounding this problem of availability is the problem of ‘collateral damage’, in which overuse of certain antibiotics, in particular the third-generation cephalosporins and the fluoroquinolones, predisposes to selection of resistant organisms such as those with extended-spectrum, β-lactamases, vancomycin-resistant enterococci and multidrug-resistant Pseudomonas. Utilisation of these classes of antibiotics within the unit as ‘workhorse’ antimicrobial agents should be discouraged [20].

Limitation of antibiotic use: i) Monotherapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Global management strategy
  5. Antibiotic selection
  6. Limitation of antibiotic use: i) Monotherapy
  7. ii) Duration
  8. iii) De-escalation and discontinuation
  9. iv) Restriction and rotation
  10. Reduction in infection
  11. Conclusion
  12. References

The limitations that exist in relation to availability of antibiotics necessitate ‘husbandry’ of this scarce resource by appropriate management of their use. A reduction of the antibiotic load in the hospital environment is the major factor likely to reduce selective pressure. There is, for example, a conflict of interest with regard to the use of monotherapy or combination therapy. Although, as has been discussed above, inadequate initial therapy increases mortality, it is not always necessary to utilise two agents to cover Gram-negative infections unless resistance levels are particularly high in a specific unit. Even in this circumstance, continuation with monotherapy once the sensitivity is known is equally effective as combination therapy, even for Pseudomonas infections [21,22].

ii) Duration

  1. Top of page
  2. Abstract
  3. Introduction
  4. Global management strategy
  5. Antibiotic selection
  6. Limitation of antibiotic use: i) Monotherapy
  7. ii) Duration
  8. iii) De-escalation and discontinuation
  9. iv) Restriction and rotation
  10. Reduction in infection
  11. Conclusion
  12. References

As most clinical parameters of sepsis resolve within the first 6 days of therapy, and decreasing the duration of empirical antibiotic use can reduce the incidence of hospital-acquired superinfection, duration should not exceed 7–8 days [23].

A recent study demonstrated the efficacy of short-course therapy (8 vs. 15 days) for ventilator-associated pneumonia (VAP). Although Pseudomonas infection was more likely to recur with the use of shorter courses, mortality was similar and there was a significant reduction in the emergence of resistance [24].

iii) De-escalation and discontinuation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Global management strategy
  5. Antibiotic selection
  6. Limitation of antibiotic use: i) Monotherapy
  7. ii) Duration
  8. iii) De-escalation and discontinuation
  9. iv) Restriction and rotation
  10. Reduction in infection
  11. Conclusion
  12. References

Similarly, the practice of routine de-escalation, once sensitivities are known, is likely to reduce resistance to the more extended-spectrum antibiotics [25]. However, this practice is difficult to apply to all patients, because a culture is not always available, resistance levels are high and physicians are often reluctant to ‘rock the boat’ if the patient is improving. In a recent study, de-escalation took place in only approximately 30% of cases, despite the existence of an active de-escalation policy [26]. Early discontinuation of antibiotics when a non-infectious aetiology has been confirmed or where prompt clinical resolution of infection has also been demonstrated to be a viable alternative. With use of this regimen, the duration of antibiotic use was reduced from 8.0 ± 5.6 days to 6.0 ± 4.9 days. Despite this, occurrence of a secondary episode of VAP, hospital mortality and the duration of intensive care unit (ICU) stay were similar [27].

iv) Restriction and rotation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Global management strategy
  5. Antibiotic selection
  6. Limitation of antibiotic use: i) Monotherapy
  7. ii) Duration
  8. iii) De-escalation and discontinuation
  9. iv) Restriction and rotation
  10. Reduction in infection
  11. Conclusion
  12. References

Restriction of certain agents has been associated, in general, with increased infection by organisms resistant to the replacement antibiotic. The long-term impact of this practice is unknown. Rahal et al. restricted use of third-generation cephalosporins to combat an outbreak of infections caused by extended-spectrum β-lactamase-producing Klebsiella. This was associated with a 44% reduction in infection and colonisation with extended-spectrum β-lactamase-producing Klebsiella, a 140% increase in the use of imipenem and a 69% increase in the incidence of imipenem-resistant Pseudomonas aeruginosa throughout the medical centre [28]. However, a 26% reduction in third-generation cephalosporin use in another study was accompanied by a 277.7% increase in cefepime usage, resulting in improved susceptibility to 3rd generation cephalosporins and infection-related hospital mortality was significantly reduced: 19% vs. 36.3% (p = 0.014) [29].

Rotation or cycling is possibly also of benefit. Gruson et al. introduced supervised antibiotic rotation and restricted the use of ceftazidime and ciprofloxacin. The selection of antibiotics was based on monthly reviews of pathogens isolated from the ICU and susceptibility patterns. Gruson et al. observed a decrease in VAP, primarily because of a reduction of episodes due to antibiotic-resistant Gram-negative bacteria, including P. aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia and Acinetobacter baumannii, and their initial results were sustained over a 5-year period [17,30]. Not all studies have demonstrated benefits from rotation, however. A more recent study by Warren et al. did not demonstrate a reduction in resistance levels using this practice [31]. However, the number of resistant isolates was underestimated at the time of study design and, as a consequence, the study was underpowered to detect emergence of resistance in the intervention phase. It is still possible that this practice may be of value, although resistance levels make it difficult to find at least four antibiotics which are likely to be effective as monotherapy in the rotational cycles.

Reduction in infection

  1. Top of page
  2. Abstract
  3. Introduction
  4. Global management strategy
  5. Antibiotic selection
  6. Limitation of antibiotic use: i) Monotherapy
  7. ii) Duration
  8. iii) De-escalation and discontinuation
  9. iv) Restriction and rotation
  10. Reduction in infection
  11. Conclusion
  12. References

The current resistance crisis means that every effort should be made to reduce the incidence of infection in the hospital, and the ICU in particular. Intensive insulin therapy, reduction in the use of urinary catheters, strictly sterile insertion of central venous catheters and efforts to reduce intubation and the duration of ventilation have all proved to be effective interventions. Similarly, maintenance of semi-recumbent posture (45°), avoidance of nasal intubation and careful disposal of condensate reduce the incidence of VAP [32–35]. Reduction in blood transfusions and, in one prospective randomised control trial, the use of leukocyte-depleted red blood cell transfusions have resulted in a reduced incidence of post-operative infections, and specifically, a reduced incidence of pneumonia in patients undergoing colorectal surgery [36,37]. Enteral nutrition is preferred over parenteral nutrition, to reduce the risk of complications related to central venous catheters and to prevent villous atrophy of the intestinal mucosa, which may increase the risk of bacterial translocation [38].

Effective infection control measures, staff education, compliance with alcohol-based hand disinfection practices and isolation to reduce cross-infection with multidrug-resistant pathogens should be maintained routinely [39,40].

Unfortunately 37% of ICU physicians and 22.3% of nurses do not adhere to preventative protocols [41,42]. Lack of resources, costs and fear of adverse effects all play a part in this failure.

Importantly, awareness of and education regarding VAP prevention do actually reduce the incidence of VAP and thereby reduce antibiotic usage [43] Staffing in the ICU is another factor contributing to the rate of sepsis. Some cost reduction initiatives, such as low nurse/patient ratios and the utilisation of poorly trained or untrained staff, are associated with lapses in infection control [44–48]. In addition, staffing of units with intensivists, as per ‘Leapfrog’ recommendations, decreases VAP rate [49].

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Global management strategy
  5. Antibiotic selection
  6. Limitation of antibiotic use: i) Monotherapy
  7. ii) Duration
  8. iii) De-escalation and discontinuation
  9. iv) Restriction and rotation
  10. Reduction in infection
  11. Conclusion
  12. References

In conclusion, we are faced with a crisis of potentially devastating proportions. No new antibiotics to combat resistant hospital-acquired infections are likely to be developed in the next decade, and thus the precious resource that we currently have must be nurtured and protected as far as is possible. Resistance cannot be eradicated, but perhaps we can prolong the lifespan of currently available antibiotics [50].

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Global management strategy
  5. Antibiotic selection
  6. Limitation of antibiotic use: i) Monotherapy
  7. ii) Duration
  8. iii) De-escalation and discontinuation
  9. iv) Restriction and rotation
  10. Reduction in infection
  11. Conclusion
  12. References
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