◆ Although appropriate antibiotics may improve survival in patients with pneumonia, the use of empirical broad-spectrum antibiotics in patients without infection is potentially harmful, facilitating colonization and superinfection with multiresistant micro-organisms. Any strategy designed to evaluate patients suspected of having developed nosocomial pneumonia (NP) should be able to withhold antimicrobial treatment in patients without pneumonia.
◆ Because even a few doses of a new antimicrobial agent can negate results of microbiological cultures, pulmonary secretions in patients suspected of having developed NP always should be obtained before new antibiotics are administered.
◆ Empirical treatment of patients with NP should be selected based on available epidemiological characteristics, information provided by direct examination of pulmonary secretions, intrinsic antibacterial activities of antimicrobial agents, and their pharmacokinetic characteristics.
◆ Altered pharmacokinetics secondary to increase in volume of distribution in critically-ill patients can result in insufficient serum β-lactam concentrations when standard dosages are administered, emphasizing the need to carefully monitor peak and trough levels of antibiotics when treating resistant pathogens.
◆ Once the microbiological data become available, antimicrobial therapy should be re-evaluated in order to avoid prolonged use of a broader spectrum of antibiotic therapy than is justified by the available information. For many patients, including those with late-onset infection, the culture data will not show the presence of highly resistant pathogens, and in these individuals, therapy can be narrowed or even reduced to a single agent in light of the susceptibility pattern of the causative pathogens without risking inappropriate treatment.
Nosocomial pneumonia (NP) is the most frequent ICU-acquired infection among patients who are treated with mechanical ventilation (MV) [1,2]. Because several studies have shown that appropriate antimicrobial treatment of patients with NP significantly improves outcome, rapid identification of infected patients and accurate selection of antimicrobial agents are important clinical goals .
NP is typically suspected when a patient has new or progressive radiographic infiltrates and clinical findings suggesting infection, such as the new onset of fever, purulent sputum, leukocytosis, increased minute ventilation, and/or a decline in arterial oxygenation. Because interpretation of chest radiographs is difficult, particularly in patients with prior abnormalities, it is also mandatory to consider the diagnosis of NP in ventilated patients who deteriorate clinically, and/or in whom vasopressors need to be increased in order to maintain blood pressure, even in the absence of a clear-cut progression of the radiographic abnormalities.
Two diagnostic algorithms can be used when NP is suspected. The first option is to treat every patient with new antibiotics, even when the likelihood of infection is low, arguing that several studies showed that the immediate initiation of appropriate antibiotics was associated with reduced mortality. The second option is to use an invasive diagnostic strategy based on quantitative cultures of distal respiratory specimens obtained using bronchoscopic or non-bronchoscopic techniques, such as bronchoalveolar lavage (BAL), in order to improve the identification of patients with true NP and facilitate decisions about whether or not to treat with antibiotics . Although using different diagnostic techniques, these two algorithms share the same goals, i.e. early, appropriate treatment of patients with true pneumonia, while avoiding antibiotics in patients without NP [1,2].
The clinical strategy
Using this strategy, antimicrobial therapy is started just after having obtained a specimen of the proximal airway secretions for qualitative microbiological testing. Initial therapy is then adjusted according to culture results and/or clinical response. Antibiotics are discontinued if and only if the following three criteria are fulfilled on day 3:
◆ Clinical diagnosis of NP is unlikely (there are no definite infiltrates found on chest radiography at follow-up and no more than one of the three following findings are present: temperature > 38.3°C, leukocytosis (>12,000/mm3) or leukopenia (<4000/mm3), and purulent tracheobronchial secretions) or an alternative non-infectious diagnosis is confirmed.
◆ Tracheobronchial aspirate culture results are non-significant.
◆ Severe sepsis or shock are not present .
While the simple qualitative culture of endotracheal aspirates (EA) is a technique with a high percentage of false-positive results due to bacterial colonization of the proximal airways in many ICU patients, recent studies using quantitative or semi-quantitative culture techniques suggest that the diagnostic accuracy of EA cultures is similar to the accuracy of more invasive techniques . The inherent advantages of these techniques are that they are also available to non-bronchoscopists, they are less expensive than bronchoscopy, and they can be performed safely in patients not receiving MV. Disadvantages include misclassification of some patients, either because the diagnosis of pneumonia is missed when EA quantitative culture results grows below the threshold defining a positive result (105–106 CFU/mL), or because a false diagnosis of pneumonia is established in patients with only airway colonization.
The invasive strategy
This strategy uses quantitative cultures of lower respiratory secretions collected by BAL, with or without a bronchoscope to define both the presence of pneumonia and the aetiological pathogen(s). Using this strategy, therapeutic decisions are tightly protocolized, using the results of direct examination of distal pulmonary samples and of quantitative cultures in deciding whether to start antibiotic therapy, which pathogens are responsible for infection, which antimicrobial agents to use, and whether to continue therapy (using a cut-off of 104 CFU/mL) .
Quantitative cultures of BAL specimens consistently yield fewer micro-organisms growing above the diagnostic threshold than are present in qualitative cultures of tracheal aspirates . Thus, when therapeutic decisions have been based on these data, fewer patients have been treated with antibiotics, and a potentially narrower spectrum of therapy was used, compared with the clinical approach, thereby limiting the emergence and dissemination of drug-resistant strains and minimizing antibiotic-related toxicity . Another compelling argument in favour of the invasive strategy is that this approach directs attention away from the lungs as the source of fever when BAL quantitative culture results are negative. Many ICU patients with negative bronchoscopic cultures have other potential sites of infection that need to be identified in order to avoid delays in initiating appropriate treatment.
The accuracy of bronchoscopic techniques is questionable in patients who have received prior antibiotics, particularly when new antibiotics have been introduced after the onset of the symptoms suggestive of NP and before pulmonary secretions were collected. However, several investigators have found that cultures of respiratory secretions are not modified in a major way when pneumonia develops in patients who have been receiving systemic antibiotics for several days before the appearance of the new pulmonary infiltrates. The reason for this appears to be that the bacteria responsible for the new infection are likely to be resistant to the antibiotics that have been used .
One major technical problem with all bronchoscopic techniques is correct selection of the sampling area in the tracheobronchial tree. The sampling area is usually selected based on the location of the radiographic infiltrate, or the bronchoscopic identification of a pulmonary segment that has purulent secretions. In patients with diffuse pulmonary infiltrates or minimal new changes in a previously abnormal chest radiograph, determining the correct segment to sample can be difficult. In such cases, sampling should be directed to the area where endobronchial abnormalities are maximal. Because autopsy studies indicate that NP frequently involves the posterior portion of the right lower lobe, this area should probably be given priority for sampling .
Summary of the evidence
Besides decision-analysis studies and a single retrospective study, five trials have used a randomized scheme to assess the effect of a diagnostic strategy on antibiotic use and outcome in patients suspected of having ventilator-associated pneumonia (VAP) . In a French study in which 413 patients were randomized, those receiving bacteriological management using BAL had a lower mortality rate on day 14, lower sepsis-related organ failure assessment scores on days 3 and 7, and less antibiotic use . Pertinently, 22 non-pulmonary infections were diagnosed in the bacteriological strategy group and only five in the clinical strategy group, suggesting that over-diagnosis of VAP can lead to errors in identifying non-pulmonary infections. More recently, a randomized trial conducted in Canada investigated the effect of different diagnostic approaches on outcomes of 740 patients suspected of having VAP . There was no difference in the 28-day mortality rate in patients in whom BAL was used, versus those in whom EA was used as the diagnostic strategy. The BAL and the EA groups also had similar rates of targeted antibiotic therapy on day 6, days alive without antibiotics, and maximum organ dysfunction scores. Unfortunately, information about how the decision algorithms were followed in the two diagnostic arms once cultures were available was not provided, raising uncertainties about how de-escalation of antibiotic therapy was pursued in patients with negative BAL cultures. Obviously, the potential benefit of using a diagnostic tool such as BAL for safely restricting unnecessary antimicrobial therapy in such a setting can only be obtained when decisions regarding antibiotics are closely linked to bacteriological results, including both direct examination and cultures of respiratory specimens.
Failure to initiate prompt appropriate and adequate therapy (the aetiological organism is sensitive to the therapeutic agent, the dose is optimal, and the correct route of administration is used) has been a consistent factor associated with increased mortality . Because pathogens associated with inappropriate initial empirical antimicrobial therapy mostly include antibiotic-resistant micro-organisms, such as Pseudomonas aeruginosa, Acinetobacter spp., Klebsiella pneumoniae, Enterobacter spp., and methicillin-resistant Staphylococcus aureus (MRSA), patients at risk for infection with these organisms should initially receive a combination of agents that can provide a very broad spectrum of coverage (see Table 117.1) . Several observational studies have now confirmed that the use of a regimen that initially combines a broad-spectrum β-lactam with an aminoglycoside increases the proportion of patients appropriately treated compared with monotherapy or to a regimen combining a β-lactam with a fluoroquinolone [8,9]. Only patients with early-onset infection, mild or moderate disease severity, and no specific risk factors for multiresistant strains, such as prolonged duration of hospitalization (>5 days), admission from a health care-related facility, recent prolonged antibiotic therapy, and specific local epidemiological data, can be treated with a narrow-spectrum drug, such as a non-pseudomonal third-generation cephalosporin [1,2].
Table 117.1 Initial antimicrobial therapy in patients with VAP
Micro-organisms usually responsible
Initial antimicrobial therapy
Early-onset VAP: (<5–7 days of MV) and no risk factors for drug-resistant pathogens (admission from a health care-related facility, recent prolonged antibiotic therapy, and specific local epidemiological data)
Streptococci, methicillin-sensitive S. aureus, H. influenzae, Moraxella catarrhalis, enteric Gram-negative (non-pseudomonal)
Non-pseudomonal 3rd-generation cephalosporin or β-lactam–β-lactamase inhibitor combination, plus one dose of an aminoglycoside in case of severe sepsis or septic shock
Late-onset and/or risk factors for drug-resistant pathogens
Difficult-to-treat Gram-negative bacilli, such as Enterobacter, Citrobacter freundii, Serratia, indole + Proteus, Morganella, Providencia, extended spectrum beta lactamase (ESBL)-producing Enterobacteriaceae, P. aeruginosa, and Acinetobacter baumannii, MRSA
Aminoglycoside (amikacin), plus one of the following:
Optimizing antimicrobial therapy
Several published reports have demonstrated the need to adjust the target dose of antimicrobial agents used in treating severe NP to individual patient’s pharmacokinetics and putative bacterial pathogens’ susceptibilities. Most investigators distinguish between antimicrobial agents that kill by a concentration-dependent mechanism (e.g. aminoglycosides and fluoroquinolones) from those that kill by a time-dependent mechanism (e.g. β-lactams and vancomycin). Altered pharmacokinetics secondary to an increase in volume of distribution in critically-ill patients can result in insufficient serum β-lactam concentrations when standard dosages are administered, emphasizing the need to carefully monitor peak and trough levels of antibiotics when treating resistant pathogens . Higher dosing regimens than those usually recommended and/or prolonged duration of infusion are frequently needed in such circumstances . Development of a priori dosing algorithms based on minimal inhibitory concentrations (MIC), patient creatinine clearance and weight, and the clinician-specified area under the inhibitory curve (AUIC) target might be a valid way to improve treatment of these patients, leading to a more precise approach than current guidelines for use of antimicrobial agents .
Focusing therapy once the agent of infection is identified
Once the results of respiratory tract and blood cultures become available, therapy can often be focused or narrowed, based on the identity of pathogens and their susceptibility to specific antibiotics, in order to avoid prolonged use of a broader spectrum of antibiotic therapy than is justified by the available information . For example, vancomycin and linezolid should be stopped if no MRSA is identified, unless the patient is allergic to β-lactams and has developed an infection caused by a Gram-positive micro-organism. Very broad-spectrum agents, such as carbapenems, piperacillin–tazobactam, and/or cefepime should also be restricted to patients with infection caused by pathogens only susceptible to these agents. Unfortunately, several studies have shown that, although de-escalation was not associated with any adverse outcomes, it was not consistently performed in many ICUs [12,13].
Switching to monotherapy at days 3–5
The two most commonly cited reasons to use combination therapy for all the antibiotic-treatment duration are to achieve synergy and prevent the emergence of resistant strains. Synergy, however, has only been clearly documented to be valuable in the therapy of P. aeruginosa or other difficult-to-treat Gram-negative bacilli (GNB) and in patients with neutropenia or bacteraemic infection, which is uncommon in NP. When combination therapy was evaluated in randomized controlled studies, its benefit was inconsistent or null, even when the results were pooled in meta-analyses or the analysis was restricted to patients infected by P. aeruginosa [14,15]. Based on these data, therapy could be safely switched to monotherapy in most patients after 3–5 days, provided that initial therapy was appropriate, clinical course appears favourable, and that microbiological data do not suggest a very difficult-to-treat micro-organism, with a very high in vitro MIC, as it can be observed with some non-fermenting-GNB.
Shortening duration of therapy
Based on data obtained from several randomized trials, an 8-day regimen can probably be standard for most patients with NP . Possible exceptions to this recommendation include immunosuppressed patients, those whose initial antimicrobial treatment was not appropriate for the causative micro-organism(s), and patients whose infection was caused by non-fermenting GNB and had no improvement in clinical signs of infection.
Many clinicians, however, remain hesitant about prescribing fewer fixed days of antibiotics for patients with NP, and would prefer to customize antibiotic duration based on the clinical course of the disease and/or using serial determinations of a biological marker of infection, such as procalcitonin (PCT). The rationale for using a biomarker to tailor antibiotic-treatment duration relies on the fact that the inflammatory response is most often proportional to infection severity. When that response is absent or low, it might be logical to discontinue antibiotics earlier. Thus, adapting antimicrobial-treatment duration to PCT kinetics seems reasonable, and has been demonstrated to be useful in several randomized trials targeting patients with acute respiratory infection, including five trials conducted in the ICU [17,18].
Nosocomial pneumonia is associated with mortality in excess of that caused by the underlying disease alone, particularly in case of infection caused by high-risk pathogens, such as P. aeruginosa and MRSA. The high level of bacterial resistance observed in patients who develop NP limits the treatment options available to clinicians and encourages the use of antibiotic regimens combining several broad-spectrum drugs, even if the pretest probability of the disease is low, because initial inappropriate antimicrobial therapy has been linked to poor prognosis. Besides its economic impact, this practice of ‘spiralling empiricism’ increasingly leads to the unnecessary administration of antibiotics in many ICU patients without true infection, paradoxically resulting in the emergence of infections caused by more antibiotic-resistant micro-organisms that are, in turn, associated with increased rates of patient mortality and morbidity. Every possible effort should therefore be made to obtain reliable pulmonary specimens for direct microscopic examination and cultures from each patient clinically suspected of having developed NP in order to be able to de-escalate treatment every time it is possible.
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