Next Article in Journal
Evolution of Bacterial Persistence to Antibiotics during a 50,000-Generation Experiment in an Antibiotic-Free Environment
Next Article in Special Issue
Drug Regimens of Novel Antibiotics in Critically Ill Patients with Varying Renal Functions: A Rapid Review
Previous Article in Journal
A Review: Antimicrobial Therapy for Human Pythiosis
Previous Article in Special Issue
Predictor of Early Administration of Antibiotics and a Volume Resuscitation for Young Infants with Septic Shock
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Antibiotics
Volume 11
Issue 4
10.3390/antibiotics11040452
antibiotics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

A Narrative Review on the Approach to Antimicrobial Use in Ventilated Patients with Multidrug Resistant Organisms in Respiratory Samples—To Treat or Not to Treat? That Is the Question

by
Lowell Ling
1,
Wai-Tat Wong
1,
Jeffrey Lipman
2,3 and
Gavin Matthew Joynt
1,*
1
Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China
2
Royal Brisbane and Women’s Hospital and Jamieson Trauma Institute, The University of Queensland, Brisbane, QLD 4029, Australia
3
Nimes University Hospital, University of Montpelier, 30900 Nimes, France
*
Author to whom correspondence should be addressed.
Antibiotics 2022, 11(4), 452; https://doi.org/10.3390/antibiotics11040452
Submission received: 10 March 2022 / Revised: 18 March 2022 / Accepted: 23 March 2022 / Published: 27 March 2022
(This article belongs to the Special Issue Antibiotic Usage in Acute Situations)
Browse Figures
Review Reports Versions Notes

Abstract

:
Multidrug resistant organisms (MDRO) are commonly isolated in respiratory specimens taken from mechanically ventilated patients. The purpose of this narrative review is to discuss the approach to antimicrobial prescription in ventilated patients who have grown a new MDRO isolate in their respiratory specimen. A MEDLINE and PubMed literature search using keywords “multidrug resistant organisms”, “ventilator-associated pneumonia” and “decision making”, “treatment” or “strategy” was used to identify 329 references as background for this review. Lack of universally accepted diagnostic criteria for ventilator-associated pneumonia, or ventilator-associated tracheobronchitis complicates treatment decisions. Consideration of the clinical context including signs of respiratory infection or deterioration in respiratory or other organ function is essential. The higher the quality of respiratory specimens or the presence of bacteremia would suggest the MDRO is a true pathogen, rather than colonization, and warrants antimicrobial therapy. A patient with higher severity of illness has lower safety margins and may require initiation of antimicrobial therapy until an alternative diagnosis is established. A structured approach to the decision to treat with antimicrobial therapy is proposed.

1. Introduction

Ventilator-associated pneumonia (VAP) is one of the most common nosocomial infections in the intensive care unit (ICU) [1]. Ventilator-associated tracheobronchitis (VAT) is considered a distinct precursor to VAP [2,3]. Both cause significant morbidity to mechanically ventilated patients [2,4,5,6]. VAP/VAT are associated with increased ventilator days, ICU and hospital length of stay [2,7]. The attributable mortality of VAP is around 3–17%, whilst risk of mortality from VAT remains controversial [8,9]. Furthermore, VAP incurs a huge cost to healthcare systems [7]. The incidence of VAP varies widely between 1.2 and 116 per 1000 ventilator days and is likely due to differences in case mix, diagnostic criteria, and the purpose of local surveillance programs [10,11].
Worldwide, the burden of multidrug resistant organisms (MDRO) is rising [12]. Antimicrobial resistance (AMR) caused 1.27 million deaths globally in 2019. The situation is no different in the ICU, which has high rates of MDRO infections. Common MDROs in the respiratory tract include multidrug resistant Pseudomonas aeruginosa and Acinetobacter baumannii, which require treatment with antimicrobial agents such as tigecycline or colistin [13]. Although the prevalence and type of MDRO-related VAP/VAT varies across different health settings [3,14,15,16], patients who have VAP due to MDRO generally have worse survival than patients with sensitive pathogens, especially when inappropriate antibiotics are used [17,18,19]. Furthermore, there are indications that the incidence of VAP caused by MDRO has increased during the current COVID-19 pandemic [20].
In the setting of a positive microbiological result, the problem of distinguishing VAP/VAT from colonization is difficult, and the lack of a universally accepted diagnostic criteria for VAP/VAT also complicates treatment decisions [6,21]. Nevertheless, the use of antimicrobial therapy for VAT is associated with reduction in progression to VAP, whilst early appropriate treatment in VAP is associated with improved survival [22,23]. Unfortunately, there are also a number of well-established harms associated with the use of antimicrobial agents in ICU [24]. Most importantly, the excessive or inappropriate use of broad-spectrum antibiotics, particularly in patients who do not have VAP, potentially promotes AMR [25]. The inappropriate use of antimicrobials negatively affects both the individual and other patients [24]. Antimicrobial use in critically ill patients has been shown to be associated with multiple drug toxicities, as well as AMR [24,26,27]. Specifically, studies have shown that the injudicious use of broad-spectrum antimicrobials for ICU-acquired infections may be associated with higher prevalence of multidrug resistant organisms and increased mortality [28,29]. While the clinical question in these studies examined the difference in outcomes between initiation of broad-spectrum antibiotics versus delayed but targeted antimicrobials, it seems plausible that withholding broad-spectrum antimicrobials in patients with likely MDRO colonization, rather than starting inappropriate broad-spectrum antimicrobial therapy, would have similar benefits.
Recent reviews have provided comprehensive summaries of epidemiological data and the recommended empirical treatment of patients with suspected or confirmed MDRO VAP/VAT [21,30]. However, we believe none explicitly detail and integrate the different elements of the clinical decision process required to determine whether antimicrobials should be initiated in ventilated patients with known MDRO respiratory isolates. Thus, the purpose of this narrative review is to discuss the relevant literature supporting the specific set of conditions that must be considered when deciding to initiate antimicrobial therapy in ventilated patients who have grown a new MDRO isolate in their respiratory specimens. As a result of this review, a comprehensive clinical framework is proposed as a guide to facilitate decisions on antimicrobial use in this setting.

2. Literature Search

A literature search was performed in MEDLINE and PubMed for published studies since 1910 on 14 March 2022 using the strategy described in Supplementary File S1. The total number of articles identified was 418, of which 89 were duplicates. All authors independently reviewed the abstract of 329 articles for inclusion and utilized the full text of 2 articles considered directly relevant to this narrative review. Following the review of references of identified articles, 80 additional articles were included. These additional articles were added after consensus with all authors; in the case of disagreement, the corresponding author made the final decision.

3. Definition of VAP/VAT

Establishing whether a patient has VAP/VAT is one of the essential steps to establish the relevance of respiratory MDRO isolates. Patients who are colonized with MDRO do not need treatment and prescription of antimicrobials targeting the MDRO may worsen AMR in this setting [24]. The classic clinical definition of VAP includes infiltrates on a chest radiograph with two of either fever, leucocytosis, or purulent sputum [31]. Unfortunately, this criterion only has a sensitivity of 69% and specificity of 75% when lung histology and culture is used as gold standard. However, it should be noted that there is considerable disagreement even amongst histopathologists on what constitutes pneumonia on histology [32].
Most individual signs lack effective diagnostic accuracy. For example, an individual sign such as fever only has 66.4% sensitivity and 53.9 specificity to diagnose VAP [33]. Similarly, leucocytosis alone is non-specific and only has 64.2% sensitivity and 59.2 specificity in identifying VAP. Furthermore, while infiltrates on plain chest radiographs are often non-specific for pneumonia, even the absence of visible infiltrates lacks the sensitivity to effectively rule out VAP [34,35]. Therefore, the Clinical Pulmonary Infection Score (CPIS) was proposed more than 30 years ago to improve the diagnosis of VAP [36]. Whilst individual components of fever, white cell count, tracheal secretions, PaO2/FiO2 ratio, microbiological sampling, and chest radiography each has poor sensitivity and specificity for VAP, the hope was that a composite score would enhance diagnostic performance. Yet, when tested, the CPIS only had 65% sensitivity and 64% specificity to diagnose VAP [37].
An alternative diagnostic approach is to use the Possible Ventilator-Associated Pneumonia (PVAP) surveillance criteria proposed by the Centers for Disease Control and Prevention (CDC) in the United States [38]. The diagnostic algorithm starts with identification of a ventilator associated event defined as a 2-day escalation of FiO2 or PEEP after a stable or decreasing trend for 2 days. If the patient has a temperature >38 or <36 °C, or white cell count ≥ 12,000 or ≤4000 cells/mm3 and a new antimicrobial is started for at least 4 days, then the patient has an infection-related ventilator-associated complication. Subsequently if the patient has a pathogen or histological evidence of pneumonia confirmed within 2 days of worsening oxygenation, then the patient is classified as having PVAP. However, because antimicrobial prescription is itself in the CDC definition, it is not possible to use the definition to help guide decisions on antimicrobial initiation. Furthermore, the CDC definition has low sensitivity for VAP which limits its utility as a clinical screening tool [39,40].
Because of the high prevalence of VAP in intensive care units, plain chest radiographs are often performed to screen for pneumonia in ventilated patients. However, the diagnostic performance of plain radiographs for VAP is poor, with a sensitivity of 24–60%, and specificity of 29–91% [41,42]. This means that plain chest radiographs are insufficiently sensitive to detect VAP. Indeed, computed tomography (CT) of the lung has better sensitivity and specificity and can improve the diagnostic yield for VAP when compared to plain radiographs [43]. However, CT scanners generally lack portability, have a substantially higher radiation exposure dose, and are inconvenient as a generic screening tool. When used selectively, CT scans may be useful in selected cases where plain chest radiographs are clear, and the significance of MDRO growth in the respiratory tract is doubtful. In this setting, CT thorax should be performed to improve diagnostic accuracy and improve the precision of the decision to treat the MDRO. The use of other lung imaging technologies, such as point of care lung ultrasound are promising investigative modalities, but current evidence on its diagnostic performance on VAP is sparse [44,45].
Similar to VAP, a universally accepted definition of VAT is lacking [21]. The commonly accepted criteria to diagnose VAT are similar to those of VAP, but with the absence of radiological evidence of pneumonia [46]. Since VAT is also associated with increased ventilator days and lengthened ICU stay, the diagnostic boundary and clinical significance of differentiating between VAT and VAP is somewhat unclear [2,3]. However, as discussed above, radiological absence of pneumonia cannot rule out VAP, and it is possible that previous studies were not sufficiently rigorous to differentiate the two entities. Whether treatment should be initiated for VAT is contentious. A detailed discussion on the merits and methods of treating VAT is beyond the scope of this review and was addressed in a recent comprehensive review [21].
The absence of definitive clinical diagnostic criteria for VAT, and as for VAP, means that treatment decisions must be made on an individual patient basis. In this review, we describe the factors that clinicians should consider in a tailored and balanced approach to determine the need for antimicrobial therapy in patients who have the presence of MDRO reported in respiratory specimens.

4. Characteristics of Respiratory Specimens

The type, quality, and timing of respiratory specimens are key factors to consider when interpreting microbiological results. Most of our understanding of microbiological sampling of the lower respiratory tract comes from clinical studies of VAP rather than from VAT. The interpretation of results for the latter is poorly described, but often assumed to be the same for VAP [47]. In both cases, specimens with >10 squamous epithelial cells should be interpreted as being the consequence of contamination from upper airway flora [48]. In parallel, distal sampling by bronchoscopy is thought to be more representative of the presence of true pathogens in the lung. In addition, endotracheal tube biofilms develop shortly after intubation and may harbor common pathogenic organisms; thus, non-invasive sampling for diagnosis of VAP via the endotracheal tube may potentially result in false positive growth secondary to contamination [49]. Nevertheless, the available clinical evidence that compares the diagnostic accuracy of bronchoscopic specimens with endotracheal samples for diagnosis of VAP remains inconclusive [50,51].
Quantitative cultures are often considered to have better diagnostic accuracy for VAP when compared to qualitative or even semi-quantitative cultures [52]. This is in part because the endotracheal tube and respiratory tract are colonized quickly after intubation [53], and quantitative cultures may be more capable of distinguishing lung parenchymal growth from upper respiratory tract contamination. Comparative studies comparing bronchoscopic and tracheal samples against the gold standard of lung biopsy have established specific thresholds that are suggestive of pathogenic growth in pneumonia (≥104 colony forming units/mL for bronchoscopic specimens, and ≥105 colony forming units/mL for tracheal aspirates) [54]. Using these thresholds may reduce, but is unlikely to eliminate the risk of attributing culture results to pathogenic growth rather than less harmful colonization of the upper airway. However, clinical evidence supporting this practice is limited [55,56]. One randomized controlled trial (RCT) found that the use of quantitative cultures from BAL or brushing compared to non-quantitative tracheal aspirates was associated with less antibiotic use and even improved survival [57]. However, another RCT concluded that patients with suspected VAP had equivalent outcomes and similar antibiotic use, regardless of whether quantitative BAL or non-quantitative tracheal aspirates were performed to guide antimicrobial therapy [58].
An important caveat is that investigations alone do not improve outcomes unless they are associated with appropriate therapeutic interventions. Observational data suggest that discontinuation of antibiotics based on quantitative culture thresholds is safe, reduces antibiotics duration, and reduces MDRO infections [59,60,61]. In patients with MDRO isolated from respiratory specimens, we recommend starting or ending targeted treatment based on semiquantitative or quantitative cultures only, and not relying on qualitative cultures alone, since the risk of subsequent increased or pan-resistance is ominous. The MDRO result should be interpreted in context of the patient’s clinical picture. Growth of MDRO despite clinical improvement may be cautiously discounted as pathogenic. Conversely, clinical deterioration with an MDRO respiratory specimen after an initial improvement in the original pathology, is more likely to suggest new infection.
All diagnostic tests should be interpreted on the basis of pre-test probability. The higher the pre-test probability, the greater the likelihood that a positive test indicates the true presence of the condition. The pre-test probability of VAP/VAT in the presence of a positive MDRO culture is very different when a sample was taken because of clinically suspected VAP/VAT when compared with the result of screening cultures taken for low grade fever, or for pan-surveillance cultures to establish the nature of local microbiological flora. In the former group, if multiple positive cultures are returned, the clinician will need to decide which pathogen is likely to explain the clinical picture. For example, if the patient also has bacteremia with the MDRO then treatment should be initiated, although only a minority of patients with VAP have concurrent bacteremia [62]. Nevertheless, antimicrobial therapy is likely necessary. On the other hand, in the latter case positive surveillance cultures in the absence of clinical findings of VAP should likely be interpreted as colonization because of the very low pre-test probability of current VAP. Furthermore, clinical assessments of current severity and the trend of severity of illness forms a key aspect of a patient’s clinical picture, and assignment of likely causality of the MDRO pathogens grown.

5. Severity of Illness

Changes in pulmonary and extra-pulmonary organ dysfunction may provide clues to determine whether the MDRO in the respiratory tract is responsible for VAP or is simply a colonizing growth. Again, the major determining factor is the pre-test probability of VAP, making the assumption that VAP causes a deterioration in pulmonary function. Key parameters to assess the severity and trajectory of pulmonary function include: PaO2/FiO2 (PF ratio), peak end-expiratory pressure (PEEP), driving pressure, and dsynchrony. A worsening PF ratio and PEEP that persists for more than 2 days, and occurring within 2 days of the MDRO growth, suggest it is responsible for the deterioration in gas exchange and ventilatory support required [38]. This strategy may minimize the chance of falsely attributing transient worsening of respiratory failure from atelectasis or sputum retention to VAP. Similarly, higher driving pressures, lower compliance, and need for initiation or escalation of sedation and paralysis for ventilator synchrony may suggest new VAP.
Whilst a deteriorating trend in pulmonary parameters is the expected clinical course when new VAP occurs, the diagnosis of VAP and antimicrobial treatment may also be warranted in patients with persistent respiratory failure, particularly when alternative diagnoses have been ruled out. The decision to treat the MDRO also depends on the physiological reserve of the patient. A patient who requires 80% FiO2 while receiving controlled ventilation and high levels of positive end expiratory pressure despite sedation and paralysis, has little reserve and room for diagnostic error. On the basis of likely risks and benefit, there may be no choice but to treat the MDRO specimen in such a patient as this may be the last opportunity to improve survival. On the contrary, a “wait and see” approach may be warranted in less ill patients to allow more time for observation and investigation, and in this way minimize overly liberal use of multiple and/or broad-spectrum antimicrobials.
Changes in extra-pulmonary organ function may also give clues as to whether the MDRO should be treated as being causative of VAP. Worsening shock with the need for progressively increased vasopressor dose, or the need for frequent fluid bolus administration, suggest a deterioration in hemodynamic function and the likelihood of systemic sepsis. Progressive acute kidney injury, hyperbilirubinemia, or thrombocytopenia also signal new onset organ dysfunction from sepsis [63]. In this context, even if there are few, or subtle clinical, radiological, or microbiological clues that suggest VAP; then treatment of the MDRO would be prudent to avoid catastrophic and irreversible deterioration. Nevertheless, attributing organ dysfunction to infection may be difficult as there is considerable interobserver variability in recognition of sepsis amongst intensivists [64]. In fact, 13% of ICU patients initially treated for sepsis do not have underlying infection [65].
An equally challenging diagnostic dilemma may occur when deterioration of respiratory function is suspected to be from secondary acute respiratory distress syndrome from an extra-pulmonary infectious or non-infectious cause. In this setting, treatment must be directed to the most likely underlying cause, although coverage of the MDRO may be required concurrently. The use of quantitative bronchoscopic cultures to confirm the diagnostic significance of MDRO in this setting should be considered.
Lastly, as a final consideration, VAP itself is not always associated with sepsis or overt organ dysfunction. It has been reported that only 30% of VAP patients have septic shock [66]. Thus, it remains necessary to treat the MDRO if there are convincing clinical signs of localized pulmonary infection as described above, even without clear evidence of systemic sepsis or septic shock.

6. Infection and Inflammatory Markers

Standard clinical observations may reveal persistent leucocytosis or leucopenia, and high fever that are suggestive of infection. Tachycardia and high minute ventilation signify raised metabolic rate, often caused by systemic inflammation or infection. However, as discussed previously, none of these findings are sufficiently sensitive nor specific, either singly or in combination to secure a diagnosis with a high degree of certainty.
A definitive biomarker able to confirm the presence of bacterial infection or sepsis with a high diagnostic performance remains elusive, despite decades of research. To date, few biomarkers have demonstrated clinical utility, and among these, the use of procalcitonin is best supported by current evidence, particularly for determining the presence of bacterial infection [67]. Studies have shown that protocolized use of procalcitonin in ICU patients with suspected infection is associated with a reduction in antibiotic duration, without causing either adverse microbiological or patient-centered outcomes [68,69,70]. Furthermore, there is increasing evidence demonstrating that the use of procalcitonin to inform the cessation of antimicrobial therapy in septic ICU patients may reduce the risk of subsequent MDRO infections, and possibly reduce mortality [71]. There is also specific data to show that procalcitonin-guided antimicrobial use reduces antibiotic exposure in patients with VAP, without any associated adverse effects [72].
Procalcitonin may be potentially useful in patients where the diagnosis of VAP is uncertain in the presence of MDRO growth, but antibiotic therapy is considered desirable on a balance of the benefit–risk assessment. In this setting, appropriate broad-spectrum antibiotics should be given first, with a plan to stop if procalcitonin levels are persistently low, or an alternative diagnosis established. Nevertheless, procalcitonin levels should always be interpreted in conjunction with other clinical factors, as diagnostic yield of PCT is limited if tested too early in the course of a new infection, or if the infection remains localized. False positives may be caused by non-infective inflammatory conditions; however, in general, procalcitonin is more specific for bacterial infections than other inflammatory markers. Procalcitonin may have an enhanced role in patients with comorbidities such as malignancy and immunosuppression, which may mask typical clinical signs of infection, although the current evidence supporting use in this setting remains scarce, and to some degree conflicting [73,74,75].

7. Comorbidities

Patients’ comorbidities may affect the interpretation of microbiological results and complicate the diagnosis of VAP. Chronic lung disease such as chronic obstructive pulmonary disease or bronchiectasis may predispose patients to respiratory tract colonization with MDRO because of the altered lung microbiological defense mechanisms, and the frequent exposure of such patients to antibiotics [76,77,78]. Patients residing in nursing homes may also be chronically colonized with MDRO [79]. In these situations, MDRO growth in respiratory samples in the absence of clinical evidence of deteriorating lung function or sepsis, makes infection less likely.
In contrast, patients who are immunosuppressed, either from hematological disease or chemotherapy, may not exhibit the classical clinical signs of pneumonia [80]. Patients may be afebrile without purulent sputum, or productive cough, and may not exhibit signs of pneumonia on examination. Furthermore, classic radiological signs of consolidation may be absent. Neutropenia may reduce the purulence of tracheal aspirates in patients who have VAP, although the evidence that this is consistently the case is lacking. Procalcitonin concentrations correlate with the presence of bacterial infection and the severity of infection in this population, but as baseline concentrations are variable, optimal concentrations have not been defined, and its use to guide antimicrobial use has not yet been adequately determined. On the contrary, patients with inflammatory airway diseases such as asthma may have chronically inflamed airways with raised neutrophil counts in the absence of pneumonia [81].

8. Alternative Diagnoses

Patients with suspected VAP may turn out to have alternative diagnoses [82,83]. Treatment thresholds are often higher for patients with MDRO growth in respiratory specimens than for patients with sensitive pathogens, because the need to use broad-spectrum antibiotics raises the risks of emergence of pan-resistant organisms, drug toxicity, drug cost, and future antibiotic option availability. Therefore, diagnostic precision should be maximized, and alternative diagnoses actively ruled out, to increase the likelihood of appropriate antimicrobial use for VAP. Thorough clinical examination and targeted investigations with echocardiography, CT and ultrasound of the thorax, abdomen, and pelvis should be considered to seek alternative diagnoses, particularly if the infective significance of the MDRO growth is uncertain within the clinical context.

9. A Practical Approach to Management

We recommend an individualized and tailored approach to the interpretation and management of MDRO growth in respiratory specimens. The decision to treat or not to treat should be informed by the pre-test probability of VAP (clinical picture and diagnostic confidence), the nature of the specimen, and the risk of rapid deterioration if antimicrobials are withheld. The decision should be one supported by reasonable certainty that VAP exists, as the potential benefits of antimicrobial treatment must be balanced against the costs of antimicrobial therapy that not only includes monetary considerations, but also the many potential antimicrobial drug side-effects, and the substantial risk of worsening AMR, both for the individual patient and the environment (Figure 1). At one end of the spectrum, patients who clearly manifest signs of infection with swinging fever, leucocytosis, and radiological signs of VAP should probably be started or continued with targeted antimicrobial therapy for the MDRO. This is even more important for patients with minimal physiological reserve and that have high risk of death, as delay in VAP treatment may be fatal [22,84,85]. At the other end of the spectrum, patients who have grown an MDRO in a respiratory sample taken for surveillance despite clinical improvement and do not exhibit signs of infection can likely be safely observed expectantly, as the MDRO is likely a colonizing organism. If such a decision is made, continued clinical vigilance is required, as the patient may progress to develop VAT or VAP. If VAT is diagnosed, early and appropriate broad-spectrum antimicrobial therapy may be justified to reduce progression to VAP [23,86].
Patients who fall between these two extremes present the greatest treatment dilemma. The accompanying algorithm is designed to provide a broad framework covering the key decision-making factors that contribute to final decision making regarding whether to treat or not to treat (Figure 2). Where there is continued diagnostic uncertainty, often associated with a restricted choice of antimicrobials in the setting of multi, or pan-resistant organisms, and moderate severity of illness, we recommend the following pragmatic approach. We recommend starting treatment with appropriate broad-spectrum antimicrobial therapy, but with reassessment of the treatment plan at a pre-determined time (usually within 2–3 days). Such reassessment should include a review of procalcitonin concentration trends, a detailed clinical assessment, and other imaging and investigations as necessary to rule out other non-VAP/VAT pathology.

10. Limitations

There are several limitations to narrative reviews that include the subjective nature of the determination of which studies to include, the way the studies are interpreted, and the conclusions drawn. Nevertheless, our literature search showed that there is limited literature specifically on whether treatment should be given when MDROs are isolated from ventilated patients’ respiratory samples. Specifically, our extensive search did not reveal any high-level evidence to guide optimal decision making that encompasses and balances all the factors discussed in this review. While a systematic review of current literature is unlikely to directly answer the question of antibiotic initiation decision making, future work should focus on capturing empirical data that can quantify the magnitude of the positive and negative outcomes of antimicrobial treatment in ventilated patients with MDRO in respiratory samples, as summarized in Figure 1 and Figure 2. Although this was not a systematic review with rigorous data extraction by independent reviewers, our aim was to synthesize current best knowledge to provide a clinical framework for facilitating frontline physicians to make the best decisions on the need for initiation of antimicrobial use in ventilated patients with MDRO respiratory isolates.

11. Conclusions

MDRO are commonly isolated from respiratory specimens of mechanically ventilated patients. Treatment decisions for suspected VAP or VAT should be tailored to clinical picture, nature of the specimen, diagnostic confidence, balanced against the cost and risk of worsening AMR. We were unable to identify any clinically focused guidelines directly addressing all aspects of the complex decision-making process required to determine whether the presence of a MDRO specimen requires antimicrobial treatment initiation. We therefore suggest a multi-consideration approach, summarized in a simplified algorithm, to assist clinical decision making.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/antibiotics11040452/s1, File S1: Literature search strategy.

Author Contributions

L.L. and G.M.J. drafted the manuscript. W.-T.W. and J.L. helped critique the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Richards, M.J.; Edwards, J.R.; Culver, D.H.; Gaynes, R.P. Nosocomial infections in combined medical-surgical intensive care units in the United States. Infect. Control Hosp. Epidemiol. 2000, 21, 510–515. [Google Scholar] [CrossRef] [PubMed]
  2. Nseir, S.; Di Pompeo, C.; Pronnier, P.; Beague, S.; Onimus, T.; Saulnier, F.; Grandbastien, B.; Mathieu, D.; Delvallez-Roussel, M.; Durocher, A. Nosocomial tracheobronchitis in mechanically ventilated patients: Incidence, aetiology and outcome. Eur. Respir. J. 2002, 20, 1483–1489. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Dallas, J.; Skrupky, L.; Abebe, N.; Boyle, W.A., 3rd; Kollef, M.H. Ventilator-associated tracheobronchitis in a mixed surgical and medical ICU population. Chest 2011, 139, 513–518. [Google Scholar] [CrossRef]
  4. Luckraz, H.; Manga, N.; Senanayake, E.L.; Abdelaziz, M.; Gopal, S.; Charman, S.C.; Giri, R.; Oppong, R.; Andronis, L. Cost of treating ventilator-associated pneumonia post cardiac surgery in the National Health Service: Results from a propensity-matched cohort study. J. Intensive Care Soc. 2018, 19, 94–100. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Melsen, W.G.; Rovers, M.M.; Groenwold, R.H.; Bergmans, D.C.; Camus, C.; Bauer, T.T.; Hanisch, E.W.; Klarin, B.; Koeman, M.; Krueger, W.A.; et al. Attributable mortality of ventilator-associated pneumonia: A meta-analysis of individual patient data from randomised prevention studies. Lancet Infect. Dis. 2013, 13, 665–671. [Google Scholar] [CrossRef]
  6. Papazian, L.; Klompas, M.; Luyt, C.E. Ventilator-associated pneumonia in adults: A narrative review. Intensive Care Med. 2020, 46, 888–906. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Safdar, N.; Dezfulian, C.; Collard, H.R.; Saint, S. Clinical and economic consequences of ventilator-associated pneumonia: A systematic review. Crit. Care Med. 2005, 33, 2184–2193. [Google Scholar] [CrossRef]
  8. Melsen, W.G.; Rovers, M.M.; Koeman, M.; Bonten, M.J. Estimating the attributable mortality of ventilator-associated pneumonia from randomized prevention studies. Crit. Care Med. 2011, 39, 2736–2742. [Google Scholar] [CrossRef]
  9. Agrafiotis, M.; Siempos, I.I.; Falagas, M.E. Frequency, prevention, outcome and treatment of ventilator-associated tracheobronchitis: Systematic review and meta-analysis. Respir. Med. 2010, 104, 325–336. [Google Scholar] [CrossRef] [Green Version]
  10. Kharel, S.; Bist, A.; Mishra, S.K. Ventilator-associated pneumonia among ICU patients in WHO Southeast Asian region: A systematic review. PLoS ONE 2021, 16, e0247832. [Google Scholar] [CrossRef]
  11. Skrupky, L.P.; McConnell, K.; Dallas, J.; Kollef, M.H. A comparison of ventilator-associated pneumonia rates as identified according to the National Healthcare Safety Network and American College of Chest Physicians criteria. Crit. Care Med. 2012, 40, 281–284. [Google Scholar] [CrossRef] [PubMed]
  12. Cassini, A.; Hogberg, L.D.; Plachouras, D.; Quattrocchi, A.; Hoxha, A.; Simonsen, G.S.; Colomb-Cotinat, M.; Kretzschmar, M.E.; Devleesschauwer, B.; Cecchini, M.; et al. Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: A population-level modelling analysis. Lancet Infect. Dis. 2019, 19, 56–66. [Google Scholar] [CrossRef] [Green Version]
  13. Grasselli, G.; Scaravilli, V.; Mangioni, D.; Scudeller, L.; Alagna, L.; Bartoletti, M.; Bellani, G.; Biagioni, E.; Bonfanti, P.; Bottino, N.; et al. Hospital-Acquired Infections in Critically Ill Patients With COVID-19. Chest 2021, 160, 454–465. [Google Scholar] [CrossRef]
  14. Sangale, A.; Vivek, B.; Kelkar, R.; Biswas, S. Microbiology of Ventilator-associated Pneumonia in a Tertiary Care Cancer Hospital. Indian J. Crit. Care Med. 2021, 25, 421–428. [Google Scholar] [CrossRef]
  15. Giantsou, E.; Liratzopoulos, N.; Efraimidou, E.; Panopoulou, M.; Alepopoulou, E.; Kartali-Ktenidou, S.; Minopoulos, G.I.; Zakynthinos, S.; Manolas, K.I. Both early-onset and late-onset ventilator-associated pneumonia are caused mainly by potentially multiresistant bacteria. Intensive Care Med. 2005, 31, 1488–1494. [Google Scholar] [CrossRef] [PubMed]
  16. Vincent, J.L.; Sakr, Y.; Singer, M.; Martin-Loeches, I.; Machado, F.R.; Marshall, J.C.; Finfer, S.; Pelosi, P.; Brazzi, L.; Aditianingsih, D.; et al. Prevalence and Outcomes of Infection Among Patients in Intensive Care Units in 2017. JAMA 2020, 323, 1478–1487. [Google Scholar] [CrossRef] [PubMed]
  17. Tedja, R.; Nowacki, A.; Fraser, T.; Fatica, C.; Griffiths, L.; Gordon, S.; Isada, C.; van Duin, D. The impact of multidrug resistance on outcomes in ventilator-associated pneumonia. Am. J. Infect. Control 2014, 42, 542–545. [Google Scholar] [CrossRef]
  18. Zheng, Y.L.; Wan, Y.F.; Zhou, L.Y.; Ye, M.L.; Liu, S.; Xu, C.Q.; He, Y.Q.; Chen, J.H. Risk factors and mortality of patients with nosocomial carbapenem-resistant Acinetobacter baumannii pneumonia. Am. J. Infect. Control 2013, 41, e59–e63. [Google Scholar] [CrossRef]
  19. Tuon, F.F.; Graf, M.E.; Merlini, A.; Rocha, J.L.; Stallbaum, S.; Arend, L.N.; Pecoit-Filho, R. Risk factors for mortality in patients with ventilator-associated pneumonia caused by carbapenem-resistant Enterobacteriaceae. Braz. J. Infect. Dis. 2017, 21, 1–6. [Google Scholar] [CrossRef] [Green Version]
  20. Baccolini, V.; Migliara, G.; Isonne, C.; Dorelli, B.; Barone, L.C.; Giannini, D.; Marotta, D.; Marte, M.; Mazzalai, E.; Alessandri, F.; et al. The impact of the COVID-19 pandemic on healthcare-associated infections in intensive care unit patients: A retrospective cohort study. Antimicrob. Resist. Infect. Control 2021, 10, 87. [Google Scholar] [CrossRef]
  21. Koulenti, D.; Arvaniti, K.; Judd, M.; Lalos, N.; Tjoeng, I.; Xu, E.; Armaganidis, A.; Lipman, J. Ventilator-Associated Tracheobronchitis: To Treat or Not to Treat? Antibiotics 2020, 9, 51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Iregui, M.; Ward, S.; Sherman, G.; Fraser, V.J.; Kollef, M.H. Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia. Chest 2002, 122, 262–268. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Nseir, S.; Favory, R.; Jozefowicz, E.; Decamps, F.; Dewavrin, F.; Brunin, G.; Di Pompeo, C.; Mathieu, D.; Durocher, A.; Group, V.A.T.S. Antimicrobial treatment for ventilator-associated tracheobronchitis: A randomized, controlled, multicenter study. Crit. Care 2008, 12, R62. [Google Scholar] [CrossRef] [Green Version]
  24. Arulkumaran, N.; Routledge, M.; Schlebusch, S.; Lipman, J.; Conway Morris, A. Antimicrobial-associated harm in critical care: A narrative review. Intensive Care Med. 2020, 46, 225–235. [Google Scholar] [CrossRef] [PubMed]
  25. Michael, C.A.; Dominey-Howes, D.; Labbate, M. The antimicrobial resistance crisis: Causes, consequences, and management. Front. Public Health 2014, 2, 145. [Google Scholar] [CrossRef] [PubMed]
  26. Armand-Lefevre, L.; Angebault, C.; Barbier, F.; Hamelet, E.; Defrance, G.; Ruppe, E.; Bronchard, R.; Lepeule, R.; Lucet, J.C.; El Mniai, A.; et al. Emergence of imipenem-resistant gram-negative bacilli in intestinal flora of intensive care patients. Antimicrob. Agents Chemother. 2013, 57, 1488–1495. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Trouillet, J.L.; Vuagnat, A.; Combes, A.; Kassis, N.; Chastre, J.; Gibert, C. Pseudomonas aeruginosa ventilator-associated pneumonia: Comparison of episodes due to piperacillin-resistant versus piperacillin-susceptible organisms. Clin. Infect. Dis. 2002, 34, 1047–1054. [Google Scholar] [CrossRef] [Green Version]
  28. Le Terrier, C.; Vinetti, M.; Bonjean, P.; Richard, R.; Jarrige, B.; Pons, B.; Madeux, B.; Piednoir, P.; Ardisson, F.; Elie, E.; et al. Impact of a restrictive antibiotic policy on the acquisition of extended-spectrum beta-lactamase-producing Enterobacteriaceae in an endemic region: A before-and-after, propensity-matched cohort study in a Caribbean intensive care unit. Crit. Care 2021, 25, 261. [Google Scholar] [CrossRef]
  29. Hranjec, T.; Rosenberger, L.H.; Swenson, B.; Metzger, R.; Flohr, T.R.; Politano, A.D.; Riccio, L.M.; Popovsky, K.A.; Sawyer, R.G. Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensive-care-unit-acquired infection: A quasi-experimental, before and after observational cohort study. Lancet Infect. Dis. 2012, 12, 774–780. [Google Scholar] [CrossRef] [Green Version]
  30. Chaïbi, K.; Péan de Ponfilly, G.; Dortet, L.; Zahar, J.-R.; Pilmis, B. Empiric Treatment in HAP/VAP: “Don’t You Want to Take a Leap of Faith?”. Antibiotics 2022, 11, 359. [Google Scholar] [CrossRef]
  31. Fabregas, N.; Ewig, S.; Torres, A.; El-Ebiary, M.; Ramirez, J.; de La Bellacasa, J.P.; Bauer, T.; Cabello, H. Clinical diagnosis of ventilator associated pneumonia revisited: Comparative validation using immediate post-mortem lung biopsies. Thorax 1999, 54, 867–873. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Corley, D.E.; Kirtland, S.H.; Winterbauer, R.H.; Hammar, S.P.; Dail, D.H.; Bauermeister, D.E.; Bolen, J.W. Reproducibility of the histologic diagnosis of pneumonia among a panel of four pathologists: Analysis of a gold standard. Chest 1997, 112, 458–465. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Fernando, S.M.; Tran, A.; Cheng, W.; Klompas, M.; Kyeremanteng, K.; Mehta, S.; English, S.W.; Muscedere, J.; Cook, D.J.; Torres, A.; et al. Diagnosis of ventilator-associated pneumonia in critically ill adult patients-a systematic review and meta-analysis. Intensive Care Med. 2020, 46, 1170–1179. [Google Scholar] [CrossRef] [PubMed]
  34. Butler, K.L.; Sinclair, K.E.; Henderson, V.J.; McKinney, G.; Mesidor, D.A.; Katon-Benitez, I.; Weaver, W.L. The chest radiograph in critically ill surgical patients is inaccurate in predicting ventilator-associated pneumonia. Am. Surg. 1999, 65, 805–809. [Google Scholar]
  35. Wunderink, R.G. Radiologic diagnosis of ventilator-associated pneumonia. Chest 2000, 117, 188S–190S. [Google Scholar] [CrossRef] [Green Version]
  36. Pugin, J.; Auckenthaler, R.; Mili, N.; Janssens, J.P.; Lew, P.D.; Suter, P.M. Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic “blind” bronchoalveolar lavage fluid. Am. Rev. Respir. Dis. 1991, 143, 1121–1129. [Google Scholar] [CrossRef]
  37. Shan, J.; Chen, H.L.; Zhu, J.H. Diagnostic accuracy of clinical pulmonary infection score for ventilator-associated pneumonia: A meta-analysis. Respir. Care 2011, 56, 1087–1094. [Google Scholar] [CrossRef] [Green Version]
  38. Ventilator-Associated Event (VAE); National Healthcare Safety Network: Washington, DC, USA, 2022.
  39. Rahimibashar, F.; Miller, A.C.; Yaghoobi, M.H.; Vahedian-Azimi, A. A comparison of diagnostic algorithms and clinical parameters to diagnose ventilator-associated pneumonia: A prospective observational study. BMC Pulm. Med. 2021, 21, 161. [Google Scholar] [CrossRef]
  40. Lachiewicz, A.M.; Weber, D.J.; van Duin, D.; Carson, S.S.; DiBiase, L.M.; Jones, S.W.; Rutala, W.A.; Cairns, B.A.; Sickbert-Bennett, E.E. From VAP to VAE: Implications of the New CDC Definitions on a Burn Intensive Care Unit Population. Infect. Control Hosp. Epidemiol. 2017, 38, 867–869. [Google Scholar] [CrossRef]
  41. Panizo-Alcaniz, J.; Frutos-Vivar, F.; Thille, A.W.; Penuelas, O.; Aguilar-Rivilla, E.; Muriel, A.; Rodriguez-Barbero, J.M.; Jaramillo, C.; Nin, N.; Esteban, A. Diagnostic accuracy of portable chest radiograph in mechanically ventilated patients when compared with autopsy findings. J. Crit. Care 2020, 60, 6–9. [Google Scholar] [CrossRef]
  42. Lefcoe, M.S.; Fox, G.A.; Leasa, D.J.; Sparrow, R.K.; McCormack, D.G. Accuracy of portable chest radiography in the critical care setting. Diagnosis of pneumonia based on quantitative cultures obtained from protected brush catheter. Chest 1994, 105, 885–887. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Claessens, Y.E.; Debray, M.P.; Tubach, F.; Brun, A.L.; Rammaert, B.; Hausfater, P.; Naccache, J.M.; Ray, P.; Choquet, C.; Carette, M.F.; et al. Early Chest Computed Tomography Scan to Assist Diagnosis and Guide Treatment Decision for Suspected Community-acquired Pneumonia. Am. J. Respir. Crit. Care Med. 2015, 192, 974–982. [Google Scholar] [CrossRef] [PubMed]
  44. Bouhemad, B.; Dransart-Raye, O.; Mojoli, F.; Mongodi, S. Lung ultrasound for diagnosis and monitoring of ventilator-associated pneumonia. Ann. Transl. Med. 2018, 6, 418. [Google Scholar] [CrossRef] [PubMed]
  45. Long, L.; Zhao, H.T.; Zhang, Z.Y.; Wang, G.Y.; Zhao, H.L. Lung ultrasound for the diagnosis of pneumonia in adults: A meta-analysis. Medicine 2017, 96, e5713. [Google Scholar] [CrossRef]
  46. Craven, D.E.; Hjalmarson, K.I. Ventilator-associated tracheobronchitis and pneumonia: Thinking outside the box. Clin. Infect. Dis. 2010, 51 (Suppl. 1), S59–S66. [Google Scholar] [CrossRef] [PubMed]
  47. Gaudet, A.; Martin-Loeches, I.; Povoa, P.; Rodriguez, A.; Salluh, J.; Duhamel, A.; Nseir, S.; TAVeM Study Group. Accuracy of the clinical pulmonary infection score to differentiate ventilator-associated tracheobronchitis from ventilator-associated pneumonia. Ann. Intensive Care 2020, 10, 101. [Google Scholar] [CrossRef] [PubMed]
  48. Morris, A.J.; Tanner, D.C.; Reller, L.B. Rejection criteria for endotracheal aspirates from adults. J. Clin. Microbiol. 1993, 31, 1027–1029. [Google Scholar] [CrossRef] [Green Version]
  49. Danin, P.E.; Girou, E.; Legrand, P.; Louis, B.; Fodil, R.; Christov, C.; Devaquet, J.; Isabey, D.; Brochard, L. Description and microbiology of endotracheal tube biofilm in mechanically ventilated subjects. Respir. Care 2015, 60, 21–29. [Google Scholar] [CrossRef] [Green Version]
  50. Sanchez-Nieto, J.M.; Torres, A.; Garcia-Cordoba, F.; El-Ebiary, M.; Carrillo, A.; Ruiz, J.; Nunez, M.L.; Niederman, M. Impact of invasive and noninvasive quantitative culture sampling on outcome of ventilator-associated pneumonia: A pilot study. Am. J. Respir. Crit. Care Med. 1998, 157, 371–376. [Google Scholar] [CrossRef]
  51. Ruiz, M.; Torres, A.; Ewig, S.; Marcos, M.A.; Alcon, A.; Lledo, R.; Asenjo, M.A.; Maldonaldo, A. Noninvasive versus invasive microbial investigation in ventilator-associated pneumonia: Evaluation of outcome. Am. J. Respir. Crit. Care Med. 2000, 162, 119–125. [Google Scholar] [CrossRef]
  52. Rattani, S.; Farooqi, J.; Jabeen, G.; Chandio, S.; Kash, Q.; Khan, A.; Jabeen, K. Evaluation of semi-quantitative compared to quantitative cultures of tracheal aspirates for the yield of culturable respiratory pathogens—A cross-sectional study. BMC Pulm. Med. 2020, 20, 284. [Google Scholar] [CrossRef] [PubMed]
  53. Durairaj, L.; Mohamad, Z.; Launspach, J.L.; Ashare, A.; Choi, J.Y.; Rajagopal, S.; Doern, G.V.; Zabner, J. Patterns and density of early tracheal colonization in intensive care unit patients. J. Crit. Care 2009, 24, 114–121. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Chastre, J.; Fagon, J.Y. Ventilator-associated pneumonia. Am. J. Respir. Crit. Care Med. 2002, 165, 867–903. [Google Scholar] [CrossRef] [PubMed]
  55. Kalil, A.C.; Metersky, M.L.; Klompas, M.; Muscedere, J.; Sweeney, D.A.; Palmer, L.B.; Napolitano, L.M.; O’Grady, N.P.; Bartlett, J.G.; Carratala, J.; et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin. Infect. Dis. 2016, 63, e61–e111. [Google Scholar] [CrossRef]
  56. Berton, D.C.; Kalil, A.C.; Teixeira, P.J. Quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilator-associated pneumonia. Cochrane Database Syst. Rev. 2014, 10, CD006482. [Google Scholar] [CrossRef] [Green Version]
  57. Fagon, J.Y.; Chastre, J.; Wolff, M.; Gervais, C.; Parer-Aubas, S.; Stephan, F.; Similowski, T.; Mercat, A.; Diehl, J.L.; Sollet, J.P.; et al. Invasive and noninvasive strategies for management of suspected ventilator-associated pneumonia. A randomized trial. Ann. Intern. Med. 2000, 132, 621–630. [Google Scholar] [CrossRef]
  58. Canadian Critical Care Trials, G. A randomized trial of diagnostic techniques for ventilator-associated pneumonia. N. Engl. J. Med. 2006, 355, 2619–2630. [Google Scholar] [CrossRef]
  59. Raman, K.; Nailor, M.D.; Nicolau, D.P.; Aslanzadeh, J.; Nadeau, M.; Kuti, J.L. Early antibiotic discontinuation in patients with clinically suspected ventilator-associated pneumonia and negative quantitative bronchoscopy cultures. Crit. Care Med. 2013, 41, 1656–1663. [Google Scholar] [CrossRef]
  60. Bonten, M.J.; Bergmans, D.C.; Stobberingh, E.E.; van der Geest, S.; De Leeuw, P.W.; van Tiel, F.H.; Gaillard, C.A. Implementation of bronchoscopic techniques in the diagnosis of ventilator-associated pneumonia to reduce antibiotic use. Am. J. Respir. Crit. Care Med. 1997, 156, 1820–1824. [Google Scholar] [CrossRef]
  61. Koenig, S.M.; Truwit, J.D. Ventilator-associated pneumonia: Diagnosis, treatment, and prevention. Clin. Microbiol. Rev. 2006, 19, 637–657. [Google Scholar] [CrossRef] [Green Version]
  62. Furtado, G.H.; Wiskirchen, D.E.; Kuti, J.L.; Nicolau, D.P. Performance of the PIRO score for predicting mortality in patients with ventilator-associated pneumonia. Anaesth. Intensive Care 2012, 40, 285–291. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Singer, M.; Deutschman, C.S.; Seymour, C.W.; Shankar-Hari, M.; Annane, D.; Bauer, M.; Bellomo, R.; Bernard, G.R.; Chiche, J.D.; Coopersmith, C.M.; et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016, 315, 801–810. [Google Scholar] [CrossRef] [PubMed]
  64. Rhee, C.; Kadri, S.S.; Danner, R.L.; Suffredini, A.F.; Massaro, A.F.; Kitch, B.T.; Lee, G.; Klompas, M. Diagnosing sepsis is subjective and highly variable: A survey of intensivists using case vignettes. Crit. Care 2016, 20, 89. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Klein Klouwenberg, P.M.; Cremer, O.L.; van Vught, L.A.; Ong, D.S.; Frencken, J.F.; Schultz, M.J.; Bonten, M.J.; van der Poll, T. Likelihood of infection in patients with presumed sepsis at the time of intensive care unit admission: A cohort study. Crit. Care 2015, 19, 319. [Google Scholar] [CrossRef] [Green Version]
  66. Koulenti, D.; Lisboa, T.; Brun-Buisson, C.; Krueger, W.; Macor, A.; Sole-Violan, J.; Diaz, E.; Topeli, A.; DeWaele, J.; Carneiro, A.; et al. Spectrum of practice in the diagnosis of nosocomial pneumonia in patients requiring mechanical ventilation in European intensive care units. Crit. Care Med. 2009, 37, 2360–2368. [Google Scholar] [CrossRef]
  67. Wirz, Y.; Meier, M.A.; Bouadma, L.; Luyt, C.E.; Wolff, M.; Chastre, J.; Tubach, F.; Schroeder, S.; Nobre, V.; Annane, D.; et al. Effect of procalcitonin-guided antibiotic treatment on clinical outcomes in intensive care unit patients with infection and sepsis patients: A patient-level meta-analysis of randomized trials. Crit. Care 2018, 22, 191. [Google Scholar] [CrossRef] [Green Version]
  68. Bouadma, L.; Luyt, C.E.; Tubach, F.; Cracco, C.; Alvarez, A.; Schwebel, C.; Schortgen, F.; Lasocki, S.; Veber, B.; Dehoux, M.; et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): A multicentre randomised controlled trial. Lancet 2010, 375, 463–474. [Google Scholar] [CrossRef]
  69. de Jong, E.; van Oers, J.A.; Beishuizen, A.; Vos, P.; Vermeijden, W.J.; Haas, L.E.; Loef, B.G.; Dormans, T.; van Melsen, G.C.; Kluiters, Y.C.; et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: A randomised, controlled, open-label trial. Lancet Infect. Dis. 2016, 16, 819–827. [Google Scholar] [CrossRef]
  70. Bloos, F.; Trips, E.; Nierhaus, A.; Briegel, J.; Heyland, D.K.; Jaschinski, U.; Moerer, O.; Weyland, A.; Marx, G.; Grundling, M.; et al. Effect of Sodium Selenite Administration and Procalcitonin-Guided Therapy on Mortality in Patients With Severe Sepsis or Septic Shock: A Randomized Clinical Trial. JAMA Intern. Med. 2016, 176, 1266–1276. [Google Scholar] [CrossRef]
  71. Kyriazopoulou, E.; Liaskou-Antoniou, L.; Adamis, G.; Panagaki, A.; Melachroinopoulos, N.; Drakou, E.; Marousis, K.; Chrysos, G.; Spyrou, A.; Alexiou, N.; et al. Procalcitonin to Reduce Long-Term Infection-associated Adverse Events in Sepsis. A Randomized Trial. Am. J. Respir. Crit. Care Med. 2021, 203, 202–210. [Google Scholar] [CrossRef]
  72. Stolz, D.; Smyrnios, N.; Eggimann, P.; Pargger, H.; Thakkar, N.; Siegemund, M.; Marsch, S.; Azzola, A.; Rakic, J.; Mueller, B.; et al. Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: A randomised study. Eur. Respir. J. 2009, 34, 1364–1375. [Google Scholar] [CrossRef] [Green Version]
  73. Yu, X.Y.; Wang, Y.; Zhong, H.; Dou, Q.L.; Song, Y.L.; Wen, H. Diagnostic value of serum procalcitonin in solid organ transplant recipients: A systematic review and meta-analysis. Transpl. Proc. 2014, 46, 26–32. [Google Scholar] [CrossRef] [PubMed]
  74. Lima, S.S.; Nobre, V.; de Castro Romanelli, R.M.; Clemente, W.T.; da Silva Bittencourt, H.N.; Melo, A.C.; Salomao, L.C.; Serufo, J.C. Procalcitonin-guided protocol is not useful to manage antibiotic therapy in febrile neutropenia: A randomized controlled trial. Ann. Hematol. 2016, 95, 1169–1176. [Google Scholar] [CrossRef] [PubMed]
  75. Chae, H.; Bevins, N.; Seymann, G.B.; Fitzgerald, R.L. Diagnostic Value of Procalcitonin in Transplant Patients Receiving Immunosuppressant Drugs: A Retrospective Electronic Medical Record-Based Analysis. Am. J. Clin. Pathol. 2021, 156, 1083–1091. [Google Scholar] [CrossRef]
  76. Nseir, S.; Di Pompeo, C.; Cavestri, B.; Jozefowicz, E.; Nyunga, M.; Soubrier, S.; Roussel-Delvallez, M.; Saulnier, F.; Mathieu, D.; Durocher, A. Multiple-drug-resistant bacteria in patients with severe acute exacerbation of chronic obstructive pulmonary disease: Prevalence, risk factors, and outcome. Crit. Care Med. 2006, 34, 2959–2966. [Google Scholar] [CrossRef]
  77. Engler, K.; Muhlemann, K.; Garzoni, C.; Pfahler, H.; Geiser, T.; von Garnier, C. Colonisation with Pseudomonas aeruginosa and antibiotic resistance patterns in COPD patients. Swiss Med. Wkly. 2012, 142, w13509. [Google Scholar] [CrossRef] [PubMed]
  78. King, P.T.; Holdsworth, S.R.; Freezer, N.J.; Villanueva, E.; Holmes, P.W. Microbiologic follow-up study in adult bronchiectasis. Respir. Med. 2007, 101, 1633–1638. [Google Scholar] [CrossRef] [Green Version]
  79. Mitchell, S.L.; Shaffer, M.L.; Loeb, M.B.; Givens, J.L.; Habtemariam, D.; Kiely, D.K.; D’Agata, E. Infection management and multidrug-resistant organisms in nursing home residents with advanced dementia. JAMA Intern. Med. 2014, 174, 1660–1667. [Google Scholar] [CrossRef]
  80. Sickles, E.A.; Greene, W.H.; Wiernik, P.H. Clinical presentation of infection in granulocytopenic patients. Arch. Intern. Med. 1975, 135, 715–719. [Google Scholar] [CrossRef]
  81. Ordonez, C.L.; Shaughnessy, T.E.; Matthay, M.A.; Fahy, J.V. Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: Clinical and biologic significance. Am. J. Respir. Crit. Care Med. 2000, 161, 1185–1190. [Google Scholar] [CrossRef]
  82. Schoemakers, R.J.; Schnabel, R.; Oudhuis, G.J.; Linssen, C.F.; van Mook, W.N.; Verbon, A.; Bergmans, D.C. Alternative diagnosis in the putative ventilator-associated pneumonia patient not meeting lavage-based diagnostic criteria. Scand. J. Infect. Dis. 2014, 46, 868–874. [Google Scholar] [CrossRef] [PubMed]
  83. Torres, A.; Carlet, J. Ventilator-associated pneumonia. European Task Force on ventilator-associated pneumonia. Eur. Respir. J. 2001, 17, 1034–1045. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Suberviola Canas, B.; Jauregui, R.; Ballesteros, M.A.; Leizaola, O.; Gonzalez-Castro, A.; Castellanos-Ortega, A. Effects of antibiotic administration delay and inadequacy upon the survival of septic shock patients. Med. Intensiva 2015, 39, 459–466. [Google Scholar] [CrossRef] [PubMed]
  85. Puech, B.; Canivet, C.; Teysseyre, L.; Miltgen, G.; Aujoulat, T.; Caron, M.; Combe, C.; Jabot, J.; Martinet, O.; Allyn, J.; et al. Effect of antibiotic therapy on the prognosis of ventilator-associated pneumonia caused by Stenotrophomonas maltophilia. Ann. Intensive Care 2021, 11, 160. [Google Scholar] [CrossRef]
  86. Nseir, S.; Martin-Loeches, I.; Makris, D.; Jaillette, E.; Karvouniaris, M.; Valles, J.; Zakynthinos, E.; Artigas, A. Impact of appropriate antimicrobial treatment on transition from ventilator-associated tracheobronchitis to ventilator-associated pneumonia. Crit. Care 2014, 18, R129. [Google Scholar] [CrossRef] [Green Version]
Antibiotics 11 00452 g001 550
Figure 1. Risk and benefits of giving and withholding treatment for patients with VAP/VAT or respiratory colonization with MDRO. Red boxes represent consequences when decision to treat or not to treat is incorrect. Green boxes represent best case scenarios even when MDRO is isolated from respiratory samples of ventilated patients. AMR, antimicrobial resistance; MV, mechanical ventilation; VAP, ventilator-associated pneumonia; VAT, ventilator-associated tracheobronchitis.
Figure 1. Risk and benefits of giving and withholding treatment for patients with VAP/VAT or respiratory colonization with MDRO. Red boxes represent consequences when decision to treat or not to treat is incorrect. Green boxes represent best case scenarios even when MDRO is isolated from respiratory samples of ventilated patients. AMR, antimicrobial resistance; MV, mechanical ventilation; VAP, ventilator-associated pneumonia; VAT, ventilator-associated tracheobronchitis.
Antibiotics 11 00452 g001
Antibiotics 11 00452 g002 550
Figure 2. Outline of key factors to be considered when deciding to treat or not to treat when a ventilated patient has a positive MDRO respiratory specimen. The final decision is based on the final weight of evidence either in favor of likely VAP or not, after systematic consideration of these multiple factors. See text for further explanation. * Does not change the likelihood of VAP diagnosis but does reduce the safety margin of withholding targeted antimicrobial therapy. MDRO, multidrug resistant organism; PEEP, positive end-expiratory pressure; P/F, PaO2/FiO2; VAP, ventilator-associated pneumonia; VAT, ventilator-associated tracheobronchitis.
Figure 2. Outline of key factors to be considered when deciding to treat or not to treat when a ventilated patient has a positive MDRO respiratory specimen. The final decision is based on the final weight of evidence either in favor of likely VAP or not, after systematic consideration of these multiple factors. See text for further explanation. * Does not change the likelihood of VAP diagnosis but does reduce the safety margin of withholding targeted antimicrobial therapy. MDRO, multidrug resistant organism; PEEP, positive end-expiratory pressure; P/F, PaO2/FiO2; VAP, ventilator-associated pneumonia; VAT, ventilator-associated tracheobronchitis.
Antibiotics 11 00452 g002
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Ling, L.; Wong, W.-T.; Lipman, J.; Joynt, G.M. A Narrative Review on the Approach to Antimicrobial Use in Ventilated Patients with Multidrug Resistant Organisms in Respiratory Samples—To Treat or Not to Treat? That Is the Question. Antibiotics 2022, 11, 452. https://doi.org/10.3390/antibiotics11040452

AMA Style

Ling L, Wong W-T, Lipman J, Joynt GM. A Narrative Review on the Approach to Antimicrobial Use in Ventilated Patients with Multidrug Resistant Organisms in Respiratory Samples—To Treat or Not to Treat? That Is the Question. Antibiotics. 2022; 11(4):452. https://doi.org/10.3390/antibiotics11040452

Chicago/Turabian Style

Ling, Lowell, Wai-Tat Wong, Jeffrey Lipman, and Gavin Matthew Joynt. 2022. "A Narrative Review on the Approach to Antimicrobial Use in Ventilated Patients with Multidrug Resistant Organisms in Respiratory Samples—To Treat or Not to Treat? That Is the Question" Antibiotics 11, no. 4: 452. https://doi.org/10.3390/antibiotics11040452

APA Style

Ling, L., Wong, W. -T., Lipman, J., & Joynt, G. M. (2022). A Narrative Review on the Approach to Antimicrobial Use in Ventilated Patients with Multidrug Resistant Organisms in Respiratory Samples—To Treat or Not to Treat? That Is the Question. Antibiotics, 11(4), 452. https://doi.org/10.3390/antibiotics11040452

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop