Pulmonary infections and resistance to antibiotics: recent information

Abstract

This yearly international meeting, ‘Infections in the Critically Ill Patient’ (3–4 February 2012, Barcelona, Spain) attended by 300 people from many different countries, was the 17th edition. This meeting gathers scientists from different horizons: microbiologists, infectious diseases specialists, intensivists and researchers in the fields of the meeting: sepsis, severe infections and pneumonia. This multidisciplinarity allows a rich cross-fertilization and outstanding discussions. This document summarizes the full day devoted to pulmonary infections and resistance to antibiotics

Keywords::

• antimicrobial resistance
• influenza
• methicillin-resistant Staphylococcus aureus
• pneumonia.

Very new papers

The reduction of the consumption of antibiotics is an important goal to be achieved in the treatment of pulmonary infections. A randomized trial comparing amoxicillin to placebo in Pakistani children aged 2–59 months has demonstrated no benefit of antibiotics for the treatment of WHO-defined nonsevere pneumonia. These results have to be taken very cautiously because the criteria of the WHO for children does not include chest x-ray and many children may not have had pneumonia [1]. The use of biomarkers in community-acquired pneumonia (CAP) has been widely investigated but still debated. Ramirez et al. measured inflammatory biomarkers in CAP patients to investigate their potential to improve minor Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) criteria for the prediction of intensive care unit (ICU) admission [2]. The additive value of biomarkers was not confirmed. However, none of the patients with three minor criteria and not admitted to ICU had procalcitonin values below a determined threshold. Clinical stability is an important parameter to monitor the evolution of patients with CAP. Aliberti et al. found an association between longer clinical stability and an increase of adverse events and deaths after discharge [3]. The results of this study show that it is important to monitor more closely the subset of patients with CAP after they are discharged. A controversial study from Kett et al. challenged the use of ATS/IDSA guidelines for the empirical therapy of patients at risk for multidrug-resistant (MDR) pathogens [4]. In fact, they found a higher mortality in patients treated according to the ATS/IDSA guidelines. The observational nature of the study and pitfalls in the follow-up of the patients preclude to accept the conclusions of this study. Chalmers and colleagues reported a large series of healthcare-associated pneumonia (HCAP) patients finding that excess mortality in that population was better linked to comorbidities rather than MDR pathogens [5]. In the field of chronic obstructive pulmonary disease exacerbation two important articles have been published in 2012. One of them suggested a decrease in exacerbations using azithromycin as prophylaxis during 1 year. The price paid for this strategy was an increase in the resistance of macrolides to Staphylococcus pneumoniae [6]. The second article demonstrated retrospectively, in a large cohort of patients with CAP, a decrease in mortality in chronic obstructive pulmonary disease patients that had received inhaled steroids [7]. This is a burning subject that probably needs prospective studies to be confirmed.

Hospital-acquired pneumonia & healthcare-associated pneumonia

Nosocomial ICU-acquired pneumonia in nonventilated patients has not been sufficiently studied. This type of hospital-acquired pneumonia has similar microbial etiology and mortality than ventilator-associated pneumonia (VAP). This information is relevant for future algorithms of treatment [8]. Artificial airway plays a key role in VAP development. Several measures concerning artificial airways have been demonstrated to be effective to decrease VAP. The type and material of endotracheal tubes, the accurate control of the tube cuff pressure, the use of subglottic aspiration, the decrease of biofilm formation and the accurate management of ventilator circuits are all issues to be taken into account [9]. Early performance of tracheostomy is a debated preventive measure of VAP. A recent Italian randomized study did not find a benefit to decrease VAP [10]. Probably, early tracheostomy could be reserved for specific populations such as neurologic patients. The current definition of HCAP is controversial. The main problem of this concept is that the risk factors released by the ATS/IDSA guidelines do not have the same weight for each one to predict the presence or absence of MDR pathogens. A new proposal of an algorithm based on the severity of disease and the presence or absence of risk factors could improve our prediction for MDR [11]. Ventilator-associated trancheobronchitis (VAT) is a potential precursor of VAP. The definition of VAT includes all the clinical elements of VAP except the presence of pulmonary infiltrates. The impact of antimicrobial treatment of VAT is a matter of debate. Two small randomized trials, one blinded and one unblinded, have found significant results in favor of administering antibiotics in VAT [12,13]. In fact, the trial from Nseir was stopped after an interim analysis due to a higher mortality in the placebo group [13]. However, a recent meta-analysis [14], including the aforementioned randomized trials and other observational studies, found that administration of systemic antibiotics (with or without inhaled ones) as opposed to placebo or no treatment in patients with VAT was not associated with lower mortality. Other outcome variables such as subsequent pneumonia and ventilator-free days had positive results. The beneficial effects of antibiotic treatment in VAT patients should be confirmed and the best duration of antimicrobial therapy should be determined in further studies.

Severe community-acquired pneumonia

The definition of severe CAP is a matter of debate. For many years severe CAP has been restricted to those patients admitted to the ICU. As one can obviously imagine, the use of this definition is subject to bias because it is influenced by the decisions of the physicians in charge and by hospital resources. The ATS, jointly with the IDSA, released two major and nine minor criteria. Having one major or three out of the minor criteria it was recommended to admit patients to the ICU. These minor criteria have been validated with acceptable results. Other criteria for severe CAP include the SMART-COP rule and the Spanish score. All severity rules have a failure in sensitivity and in addition do not specifically weigh the potential contribution of complications or decompensated comorbidity to pneumonia severity. In fact, those patients needing ICU admission after 48 h of ward admission are twice as like to die compared with those admitted during the first 12 h after arrival to the hospital. The recently described risk of early admission-ICU index score provides tools for monitoring patients that do not need admission to the ICU in the first 24 h but have potential risk for complications. This score has been also validated [15].

Diagnostic tests

Having molecular tests that could provide rapid microbiological information is a challenge. Having sensitive and specific rapid tests for the clinical practice would completely change our current approach about the management of pneumonia. The future implementation of these tests would improve the outcome of pneumonia as has been suggested in the literature. Now it is time to translate this new approach to clinical practice.

Management of methicillin-resistant Staphylococcus aureus pneumonia

The challenges in treating nosocomial methicillin-resistant S. aureus (MRSA) pneumonia are multiple, including the limitations of current therapeutic agents. Vancomycin represents the most commonly used agent for MRSA pneumonia, but effective therapy is challenged by rising MIC values for the target organism, with the realization of potentially reduced efficacy once values rise above 1 mg/l [16]. At the same time, when efforts are made to optimize vancomycin dosing by pushing trough levels to 15–20 mg/l, the risk of nephrotoxicity rises, particularly in critically ill patients. Current guidelines recommend the use of either vancomycin or linezolid, with no preference for either, but telavancin is not a currently used option, although it may be more effective than vancomycin, once MIC values exceed 1 mg/l.

In selecting the most effective therapy for VAP, there are new data that suggest a potential advantage for linezolid over optimally dosed vancomycin for patients with documented MRSA pneumonia [17]. This study included patients with both VAP and HCAP, and showed that linezolid led to a significantly higher rate of clinical cure in the per-protocol population and at the end of study (7–30 days after completing therapy), but with no difference in mortality. However, the mortality rate with vancomycin was lower in this study than in prior studies, whereas the linezolid group had the same mortality as in previous investigations. The ‘improved’ results with vancomycin may have reflected optimal dosing, the presence of very few organisms with MIC values >1 mg/l and changes in care compared with the past. The new data raise the issue of whether linezolid should be used routinely in place of vancomycin, or should be reserved for patients either not responding to vancomycin, or for those documented to have organisms with high MIC values.

Lessons learned from management of H1N1 influenza

The H1N1 influenza pandemic provided an experience with epidemic viral infection that served to be instructive in a number of areas, including the use of scoring systems to predict mortality and the value of adjunctive therapies such as extracorporeal membrane oxygenation and corticosteroids. Martin-Loeches and colleagues compared the experience with the original pandemic in 2009 in Spain with the experience with the infection in the post-pandemic years of 2010–2011 [18]. Although more patients, 648 in all, were infected in 2009, there were still 349 patients infected in the postpandemic period, and these individuals were older, had more comorbidities, were more severely ill and had a higher mortality. The explanation for these findings may be that less vulnerable populations who were infected in the original pandemic were now immune to H1N1 and thus not affected, while at the same time, clinicians were less alert to the problems of influenza after the original pandemic. This experience emphasizes the importance of always remaining alert to epidemic viral infection, particularly in high-risk individuals. The Spanish experience with H1N1 influenza also demonstrated that pneumonia severity scoring systems, such as CURB-65 and the pneumonia severity index, were not valuable for helping site-of-care decisions in patients with pneumonia and influenza, particularly because they could not reliably define low-mortality risk patients [19]. In Spain, there was some experience with supportive care involving extracorporeal membrane oxygenation, which was used in nine patients, leading to a survival rate of 44.4%, suggesting that it could be a possible rescue technique [20]. The use of coadjuvant treatment with steroids has been advocated to improve outcomes in H1N1 pneumonia. Three manuscripts published this year have not only found no benefit, but also an increase of nosocomial infections [21–23]. From this information it seems unjustified to use coadjuvant steroids in H1N1 CAP.

An intervention trial to manage multidrug-resistant bacteria in the critically ill patients

The MOSAR study is a multicenter, multinational program to monitor, diagnose and control infection with MDR bacteria, particularly MRSA, vancomycin-resistant enterococcus, Enterobacteriaceae and extended-spectrum β-lactamase-producing Gram negatives. The program includes multiple components focusing on intervention trials to eliminate ICU-resistant bacteria, new methods for rapid recognition of these pathogens and studies to evaluate modes of bacterial transmission. The intervention trials are ongoing, and the ICU setting has focused on hygiene, chlorhexidine body washes, screening for MDR pathogens and isolating and cohorting of patients with MDR pathogens. There are plans to study the problem of MDR pathogens in surgical, rehabilitation and medical patients. This type of multicenter study is likely to yield important information about ways to best manage MDR pathogen risks, particularly if it can lead to rapid diagnostic and screening tools.

Ethical issues in the use of antibiotics in the intensive care unit

One of the factors contributing to antimicrobial resistance in the ICU is antibiotic therapy for patients with possible infection at the end of life. While antibiotics can be life-saving for serious infection, sometimes they are used without documented infection or benefit, resulting in over-usage with the selection of antibiotic resistance [24]. It can be argued that the use of antibiotics for those who are receiving futile, end-of-life care is unethical, since it can lead to antibiotic resistance that may make the treatment of other patients impossible, since no effective therapies may be available. Antibiotics present a unique dilemma, since they are not a limited resource, as for example ICU beds are, yet their use for futile care can deprive other patients in the ICU of an optimal chance for recovery, because their use in the setting of futile care may promote antibiotic resistance and make them useless for other patients. If antibiotics are used in the ICU, it must be with strong justification and not simply of symbolic value, or in response to the emotional needs of patients and families, because of the potential for serious collateral harm to others. Complexity arises because physicians caring for individuals at the end of life are obligated to satisfy the needs of the patient, and not the greater societal good. Hospitals and physicians need to discuss these issues, and find appropriate mechanisms for resolving these potential conflicts. One such approach may be to involve another team of physicians, such as a palliative care consult service, to discuss withdrawal of medical interventions (including antibiotics), whereas the attending physician focuses on determining appropriate medical indications for the interventions.

Financial & competing interests disclosure

MS Niederman has received honoraria for consulting and lecturing from Pfizer Inc. and Merck Inc. The authors have no other 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 apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.