Antibiotic Therapy of Ventilator-Associated Pneumonia: In Search of the Magic Bullet

Abstract

Pneumonia occurring during mechanical ventilation, the so-called ventilator-associated pneumonia (VAP), is the major cause of infection in critically ill patients who are receiving mechanical ventilation. Accordingly, lower respiratory tract infection is the major reason for prescribing antibiotics to patients in the ICU.1Bergmans DC Bonten MJM Gaillard CA et al.Indications for antibiotic use in ICU patients: a one-year prospective surveillance.J Antimicrob Chemother. 1997; 39: 527-535Crossref PubMed Scopus (155) Google Scholar Given the current trends in antimicrobial resistance,2National Nosocomial Infections Surveillance System Intensive Care Antimicrobial Resistance Epidemiology (ICARE) Surveillance Report, data summary from January 1996 through December 1997: a report from the National Nosocomial Infections Surveillance (NNIS) System.Am J Infect Control. 1999; 27: 279-284Abstract Full Text Full Text PDF Scopus (101) Google Scholar the fact that ICUs are the major source and reservoir of resistant strains3Kollef MH Fraser VJ Antibiotic resistance in the intensive care unit.Ann Intern Med. 2001; 134: 298-314Crossref PubMed Scopus (388) Google Scholar and inasmuch as resistance is, at least in part, linked to antibiotic use, there is both a strong rationale and an incentive for designing antibiotic policies for the management of infection in the ICU that are aimed at controlling or reducing patient resistance, especially for therapy in patients with respiratory tract infections.3Kollef MH Fraser VJ Antibiotic resistance in the intensive care unit.Ann Intern Med. 2001; 134: 298-314Crossref PubMed Scopus (388) Google Scholar Toward this end, several approaches have been advocated, including restrictive formularies, the rotation of antibiotics, and the use of specific diagnostic techniques, which result in the empirical treatment of fewer patients with clinically suspected pneumonia.4Bonten MJM Bergmans DC Stobberingh EE et al.Implementation of bronchoscopic techniques in the diagnosis of ventilator-associated pneumonia to reduce antibiotic use.Am J Respir Crit Care Med. 1997; 156: 1820-1824Crossref PubMed Scopus (132) Google Scholar5Fagon JY Chastre J Wolff M et al.Invasive and noninvasive strategies for management of suspected ventilator-associated pneumonia: a randomized trial.Ann Intern Med. 2000; 132: 621-630Crossref PubMed Scopus (730) Google Scholar However, a number of studies6Dupont H Mentec H Sollet JP et al.Impact of appropriateness of initial antibiotic therapy on the outcome of ventilator-associated pneumonia.Intensive Care Med. 2001; 27: 355-362Crossref PubMed Scopus (261) Google Scholar7Rello J Gallego M Mariscal D et al.The value of routine microbial investigation in ventilator-associated pneumonia.Am J Respir Crit Care Med. 1997; 156: 196-200Crossref PubMed Scopus (442) Google Scholar8Ruiz M Torres A Ewig S et al.Noninvasive vs invasive microbial investigation in ventilator-associated pneumonia: evaluation of outcome.Am J Respir Crit Care Med. 2000; 162: 119-125Crossref PubMed Scopus (285) Google Scholar9Sanchez-Nieto JM Torres A Garcia-Cordoba F et al.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: 371-376Crossref PubMed Scopus (324) Google Scholar have emphasized the importance of adequate early antibiotic therapy in the management of patients who are clinically suspected of infection and have shown that patients who are initially treated inadequately had poorer outcomes than did those receiving adequate therapy at the beginning. One study10Luna CM Vujacich P Niederman MS et al.Impact of BAL data on the therapy and outcome of ventilator-associated pneumonia.Chest. 1997; 111: 676-685Abstract Full Text Full Text PDF PubMed Scopus (822) Google Scholar has even suggested that adequate therapy administered before the clinical suspicion of pneumonia (an objective that obviously is achievable only by chance alone) was associated with a better prognosis. Inadequate empiric antimicrobial therapy can occur because of the presence of unanticipated species that are not covered by the regimen selected but is mostly due to unanticipated resistance.11Kollef MH Sherman G Ward S et al.Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients.Chest. 1999; 115: 462-474Abstract Full Text Full Text PDF PubMed Scopus (1568) Google Scholar Clinicians, therefore, are faced with the following dilemma: treat early all patients who have a clinical suspicion of VAP, preferably with broad-spectrum combination therapy to cover most likely species and to overcome potential resistance problems, thereby taking the risk of fostering resistance12Trouillet JL Chastre J Vuagnat A et al.Ventilator-associated pneumonia caused by potentially drug-resistant bacteria.Am J Respir Crit Care Med. 1998; 157: 531-539Crossref PubMed Scopus (781) Google Scholar; or make a more conservative, selective, and prudent use of antibiotics that exposes some patients to a potential delay in therapy and to suboptimal management. Practically speaking, there are actually two challenges for the clinician, as follows: to decide when and which patient should be treated; then to select which antibiotic therapy to prescribe empirically. One approach to resolve or, to say it more appropriately, to bypass the first challenge has been illustrated by the study of Singh et al.13Singh N Rogers P Atwood CW et al.Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit: a proposed solution for indiscriminate antibiotic prescription.Am J Respir Crit Care Med. 2000; 162: 505-511Crossref PubMed Scopus (850) Google Scholar Those investigators tested a strategy in which all patients initially were treated empirically (in this instance with ciprofloxacin), then antibiotic therapy was withdrawn after 3 days in patients who had a low likelihood of pneumonia to start with, as assessed by the clinical pulmonary infection score (CPIS),14Pugin J Auckenthaler R Mili N et al.Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and non-bronchoscopic “blind” bronchoalveolar lavage fluid.Am Rev Respir Dis. 1991; 143: 1121-1129Crossref PubMed Google Scholar and who have maintained a low score (ie, < 6) after 3 days of therapy. This approach, while treating all patients who are suspected of pneumonia somewhat indiscriminately, has the merit of limiting the administration of unnecessary antibiotic therapy to some extent. A more sophisticated approach is to combine the clinical likelihood of pneumonia (based on a variable combination of measurements of purulent tracheal secretions, pulmonary infiltrates, temperature, leukocytosis, and Pao2/fraction of inspired oxygen ratio, and their recent alterations, as is the case with the CPIS) with the results of direct examinations of respiratory tract secretion specimens, such as Gram stains,15Blot F Raynard B Chachaty E et al.Value of gram stain examination of lower respiratory tract secretions for early diagnosis of nosocomial pneumonia.Am J Respir Crit Care Med. 2000; 162: 1731-1737Crossref PubMed Scopus (85) Google Scholar or the direct examination of, for example, bronchoscopic BAL fluid samples,16Chastre J Fagon JY State of the art: ventilator-associated pneumonia.Am J Respir Crit Care Med. 2002; 165: 867-903Crossref PubMed Scopus (2173) Google Scholar and the clinical severity of the systemic response to infection17Bonten MJM Froon AHM Gaillard CA et al.The systemic inflammatory response in the development of ventilator-associated pneumonia.Am J Respir Crit Care Med. 1997; 156: 1105-1113Crossref PubMed Scopus (88) Google Scholar18Froon AHM Bonten MJM Gaillard CA et al.Prediction of clinical severity and outcome of ventilator-associated pneumonia: comparison of simplified acute physiology score with systemic inflammatory mediators.Am J Respir Crit Care Med. 1998; 158: 1026-1031Crossref PubMed Scopus (52) Google Scholar to decide whether or not to initiate antibiotic therapy in a patient having a clinical suspicion of pneumonia. Once a decision to treat has been made, how should the selection of empiric antibiotic therapy proceed? Although ciprofloxacin has proved to be effective in limiting unnecessary antibiotic use in the specific setting of the study performed by Singh et al,13Singh N Rogers P Atwood CW et al.Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit: a proposed solution for indiscriminate antibiotic prescription.Am J Respir Crit Care Med. 2000; 162: 505-511Crossref PubMed Scopus (850) Google Scholar this choice can be questioned. Ciprofloxacin is certainly very effective in most cases against enterobacteriaceae and Haemophilus influenzae, and is usually effective against Staphylococcus aureus (although many methicillin-resistant strains have an associated resistance to fluoroquinolones), but is suboptimal therapy for streptococci, including pneumococci, and for Pseudomonas aeruginosa, at least when used alone.19Fink MP Snydman DR Niederman MS et al.Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin.Antimicrob Agents Chemother. 1994; 38: 547-557Crossref PubMed Scopus (426) Google Scholar In this issue of CHEST (see page 835), Fowler et al suggest that an anti-Pseudomonas, extended-spectrum penicillin combined with a β-lactamase inhibitor (ie, piperacillin-tazobactam) could be the most appropriate empiric therapy for suspected VAP. In this study, the authors analyzed empiric therapy and outcomes in 156 patients with suspected VAP. By Cox regression analysis, they found a lower risk of hospital mortality (odds ratio [OR], 0.41; 95% confidence interval [CI], 0.21 to 0.80) in patients to whom initial empiric therapy with piperacillin-tazobactam was administered by their attending physicians, as well as a strong trend toward reduced mortality (OR, 0.43; 95% CI, 0.16 to 1.11) in patients receiving aminoglycosides, compared to patients receiving other antibiotics. Piperacillin-tazobactam was the drug most commonly administered in this cohort (63%), followed by fluoroquinolones (57%), vancomycin (47%), cephalosporins (28%), and aminoglycosides (25%). As in most studies of patients with VAP, a majority of patients (54%) actually received combination therapy. Other predictors of hospital mortality that were identified in this study were hepatic failure (OR, 4.6), an immunocompromised status (OR, 2.68), and APACHE (acute physiology and chronic health evaluation) II score (OR, 1.12). The authors were unable to demonstrate improved outcome associated with appropriate vs inappropriate therapy, or with combination therapy vs monotherapy. As for many studies of this kind, in which several therapeutic approaches are compared within the context of an observational study, the results are difficult to interpret, and such observations do not have the strengths of those derived from randomized controlled trials. Many of the patients studied by Fowler et al received combination therapy, including 45% of those treated with piperacillin-tazobactam, and the authors provide no clue to account for the marked superiority of piperacillin-tazobactam compared to the effects of other antibiotics and its impact on mortality. As noted earlier, this did not appear to be associated with more adequate therapy. However, the very high treatment adequacy rate recorded in this study (92%) and the variety of antibiotics that were examined likely explain why the variable “appropriateness of therapy” was not found as a prognostic factor. It also should be noted that a diagnosis of VAP was microbiologically confirmed with “acceptable specimens” (ie, using tracheal aspirates only) in only 74% of suspected cases, so that the etiology of infection (or even its reality) in the cohort is uncertain, making the judgment on adequacy uncertain and limited to a fraction of the population. The favorable results associated with piperacillin-tazobactam may have been due to its broad spectrum of activity, encompassing the major microorganisms associated with VAP, including streptococci, staphylococci (non-methicillin-resistant), enterobacteriaceae, and P aeruginosa, as well as anaerobes. Another hypothesis would be that piperacillin-tazobactam therapy resulted in a lower level of resistance emergence and superinfection during or after therapy, as has been suggested in one previous study,20Brun-Buisson C Sollet JP Schweich H et al.Treatment of ventilator-associated pneumonia with piperacillin-tazobactam/amikacin vs ceftazidime/amikacin: a multicenter, randomized controlled trial.Clin Infect Dis. 1998; 26: 346-354Crossref PubMed Scopus (102) Google Scholar but this was not documented by Fowler et al. Most randomized controlled trials comparing new regimens with established ones in patients with hospital-acquired pneumonia tend to show equivalence of the regimens tested, and none shows an effect on mortality. Several such trials20Brun-Buisson C Sollet JP Schweich H et al.Treatment of ventilator-associated pneumonia with piperacillin-tazobactam/amikacin vs ceftazidime/amikacin: a multicenter, randomized controlled trial.Clin Infect Dis. 1998; 26: 346-354Crossref PubMed Scopus (102) Google Scholar21Joshi M Bernstein J Solomkin J et al.Piperacillin/tazobactam plus tobramycin vs ceftazidime plus tobramycin for the treatment of patients with nosocomial lower respiratory tract infection: Piperacillin/tazobactam Nosocomial Pneumonia Study Group.J Antimicrob Chemother. 1999; 43: 389-397Crossref PubMed Scopus (73) Google Scholar22Alvarez-Lerma F Insausti-Ordenana J Jorda-Marcos R et al.Efficacy and tolerability of piperacillin/tazobactam vs ceftazidime in association with amikacin for treating nosocomial pneumonia in intensive care patients: a prospective randomized multicenter trial.Intensive Care Med. 2001; 27: 493-502Crossref PubMed Scopus (55) Google Scholar have compared piperacillin-tazobactam with ceftazidime (both in combination with an aminoglycoside) and have found that, overall, the former was at least as effective and possibly more effective than the latter. The results recorded by Fowler et al, although inordinately favorable, as is often the case in nonrandomized studies, are nevertheless consistent with those from these trials. In view of these very encouraging results, should piperacillin-tazobactam become the standard therapy for all patients with VAP? The authors adequately caution against this view. In addition to the presence of risk factors that are specific to the underlying disease of patients, it has become clear that there are three important determinants of the etiology of VAP that can be used to guide the selection of initial therapy, as follows: the timing of onset of pneumonia relative to ICU (or preferably hospital) admission; the prior administration of antibiotics; and unit-specific local epidemiologic factors. The distinction between early pneumonia (ie, after < 5 to 7 days in the ICU) and late-onset pneumonia is a major determinant of the etiology, provided that the patient has not spent some time in the hospital before ICU admission or has had a recent hospitalization. In early-onset cases, the clinician can be fairly confident that “normal flora” (ie, Streptococcus pneumoniae and other streptococci, H influenzae, S aureus, and possibly anaerobes in selected circumstances) are involved, and there is no need for the administration of an antipseudomonal, broad-spectrum penicillin combined with a β-lactamase inhibitor or of ciprofloxacin. Therapy with a first-generation cephalosporin or a combination of ampicillin with a β-lactamase inhibitor will suffice. However, if the patient has received antibiotics for some time, especially broad-spectrum ones,12Trouillet JL Chastre J Vuagnat A et al.Ventilator-associated pneumonia caused by potentially drug-resistant bacteria.Am J Respir Crit Care Med. 1998; 157: 531-539Crossref PubMed Scopus (781) Google Scholar then the flora colonizing and infecting the respiratory tract is much more likely to have been modified to include “hospital organisms,” such as Klebsiella, Enterobacter, and particularly P aeruginosa, all of which are likely to be resistant to any antibiotics that had been administered previously. The worst-case scenario is for the patient to have received several extended courses of antibiotics, and, when presenting with pneumonia occurring late after hospital/ICU admission, to be exposed to an environment in which resistant organisms such as Acinetobacter, Pseudomonas, methicillin-resistant S aureus, or vancomycin-resistant Enterococcus are endemic. In this instance, it is very difficult to predict the microorganisms that may be involved and their susceptibility profile, so that a three-agent combination empiric therapy with a β-lactam, an aminoglycoside, and a glycopeptide is commonly prescribed pending culture results, unless a more targeted approach can be guided by the direct examination of reliable respiratory tract specimens showing a single population. In such settings, piperacillin-tazobactam or any other single drug is unlikely to cover adequately all microorganisms involved. Again, the high rate of adequate initial empiric therapy (92%), despite the fact that most patients were treated for a suspicion of late-onset pneumonia (after a mean 11 days of mechanical ventilation), suggests that the study was conducted in an environment that was relatively preserved from antimicrobial resistance or that the population was at low risk of resistance to start. This fact again highlights the importance of the local surveillance of the epidemiology of microorganisms in devising antibiotic strategies in a specific ICU.23Rello J Sa-Borges M Correa H et al.Variations in etiology of ventilator-associated pneumonia across four treatment sites: implications for antimicrobial prescribing practices.Am J Respir Crit Care Med. 1999; 160: 608-613Crossref PubMed Scopus (321) Google Scholar Nevetheless, the findings by Fowler et al confirm that piperacillin-tazobactam often can provide adequate empiric therapy in many patients who are suspected of late-onset pneumonia, as already has been suggested in the controlled studies20Brun-Buisson C Sollet JP Schweich H et al.Treatment of ventilator-associated pneumonia with piperacillin-tazobactam/amikacin vs ceftazidime/amikacin: a multicenter, randomized controlled trial.Clin Infect Dis. 1998; 26: 346-354Crossref PubMed Scopus (102) Google Scholar21Joshi M Bernstein J Solomkin J et al.Piperacillin/tazobactam plus tobramycin vs ceftazidime plus tobramycin for the treatment of patients with nosocomial lower respiratory tract infection: Piperacillin/tazobactam Nosocomial Pneumonia Study Group.J Antimicrob Chemother. 1999; 43: 389-397Crossref PubMed Scopus (73) Google Scholar22Alvarez-Lerma F Insausti-Ordenana J Jorda-Marcos R et al.Efficacy and tolerability of piperacillin/tazobactam vs ceftazidime in association with amikacin for treating nosocomial pneumonia in intensive care patients: a prospective randomized multicenter trial.Intensive Care Med. 2001; 27: 493-502Crossref PubMed Scopus (55) Google Scholar comparing piperacillin-tazobactam with ceftazidime. It should not, however, be considered a magic bullet. In some institutions, this drug cannot be used in confidence, especially in patients having previously received an extended-spectrum penicillin24Carmeli Y Troillet N Eliopoulos GM et al.Emergence of antibiotic-resistantPseudomonas aeruginosa: comparison of risks associated with different antipseudomonal agents.Antimicrob Agents Chemother. 1999; 43: 1379-1382PubMed Google Scholar or even fluoroquinolones.25Trouillet JL Vuagnat A Combes A et al.Pseudomonas aeruginosaventilator-associated pneumonia: comparison of episodes due to piperacillin-resistant vs piperacillin-susceptible organisms.Clin Infect Dis. 2002; 34: 1047-1054Crossref PubMed Scopus (143) Google Scholar While the latter class is more likely to foster the selection of antibiotic-resistant strains in the ICU environment, the routine and systematic use of a drug having marked antianaerobic activity such as piperacillin-tazobactam may put patients at risk for selection of resistance in a favorable environment.26Donskey CJ Chowdhry TK Hecker MT et al.Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients.N Engl J Med. 2000; 343: 1925-1932Crossref PubMed Scopus (533) Google Scholar There is room for individualized therapy of clinically suspected VAP in many patients, varying the agents prescribed according to the specific condition and risk factors they present with, the antecedent antibiotics, local epidemiologic surveillance, and the microbiological information available at the time of the prescription.