Antimicrobial Therapy of Ventilator-Associated Pneumonia: How To Select an Appropriate Drug Regimen

Abstract

Ventilator-associated pneumonia (VAP) refers to nosocomial pneumonia developing in a patient receiving mechanical ventilation. VAP is recognized as being one of the leading causes of death from hospital-acquired infections in the ICU setting.1Vincent JL Bihari DJ Suter PM et al.The prevalence of nosocomial infection in intensive care units in Europe: results of the European Prevalence of Infection in Intensive Care (EPIC) Study: EPIC International Advisory Committee.JAMA. 1995; 274: 639-644Crossref PubMed Scopus (2218) Google Scholar, 2Kollef MH Sharpless L Vlasnik J et al.The impact of noscomial infections on patient outcomes following cardiac surgery.Chest. 1997; 12: 666-675Abstract Full Text Full Text PDF Scopus (234) Google Scholar The estimated prevalence of VAP ranges from 10 to 65% with case fatality rates of 13 to 55%.3Craven DE Steger KA Ventilator-associated bacterial pneumonia: challenges in diagnosis, treatment, and prevention.New Horiz. 1998; 6: S30-S45PubMed Google Scholar, 4Kollef MH Ventilator-associated pneumonia: an update for clinicians.Respir Care. 1995; 40: 1130-1140PubMed Google Scholar Additionally, several clinical studies have demonstrated an attributable mortality associated with VAP that is independent of patients’ underlying diagnoses and severity of illness at the time of ICU admission.5Leu HS Kaiser DL Mori M et al.Hospital-acquired pneumonia: attributable mortality and morbidity.Am J Epidemiol. 1989; 129: 1258-1267Crossref PubMed Scopus (290) Google Scholar, 6Fagon JY Chastre J Hance AJ et al.Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay.Am J Med. 1993; 94: 281-288Abstract Full Text PDF PubMed Scopus (1009) Google Scholar The occurrence of VAP also increases the costs associated with hospitalization. Several economic analyses estimate the excess medical costs attributed to an episode of VAP to be > $5,000 with prolongation of the hospital stay from 6 to > 30 days.7Public health focus: Surveillance, prevention, and control of nosocomial infections.MMWR. 1992; 41: 783-787PubMed Google Scholar, 8Jarvis WR Selected aspects of the socioeconomic impact of nosocomial infections: morbidity, mortality, cost, and prevention.Infect Control Hosp Epidemiol. 1996; 17: 552-557Crossref PubMed Scopus (459) Google Scholar, 9Boyce JM Potter-Bynoe G Dziobek L et al.Nosocomial pneumonia in Medicare patients: hospital costs and reimbursement patterns under the prospective payment system.Arch Intern Med. 1991; 151: 1109-1114Crossref PubMed Scopus (72) Google Scholar Recently, the importance of providing early effective antimicrobial therapy for patients with VAP has been highlighted by several clinical investigations.10Luna 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 (817) Google Scholar, 11Alvarez-Lerma F Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit: ICU-Acquired Pneumonia Study Group.Intensive Care Med. 1996; 22: 387-394Crossref PubMed Scopus (589) Google Scholar, 12Rello 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 (439) Google Scholar, 13Kollef MH Ward S The influence of mini-BAL cultures on patient outcomes: implications for the antibiotic management of ventilator associated pneumonia.Chest. 1998; 113: 412-420Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar Once VAP develops, treatment is usually supportive along with the administration of antibiotics. The selection of antimicrobial agents for the initial empiric treatment of VAP appears to be an important determinant of clinical outcomes, especially hospital mortality. Luna and colleagues10Luna 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 (817) Google Scholar examined 132 patients requiring mechanical ventilation with clinically suspected VAP. A total of 50 patients with positive BAL cultures received empiric antibiotic therapy prior to obtaining the BAL culture results. Patients who received adequate antibiotic therapy (n = 16), as defined by the BAL culture results, had a significantly lower mortality rate compared with patients receiving inadequate antibiotic therapy (n = 34) (37.5% vs 91.2%; p < 0.001). Alvarez-Lerma11Alvarez-Lerma F Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit: ICU-Acquired Pneumonia Study Group.Intensive Care Med. 1996; 22: 387-394Crossref PubMed Scopus (589) Google Scholar evaluated the appropriateness of antimicrobial therapy in 430 patients with VAP receiving antibiotic treatment. The attributable mortality from VAP was significantly greater among patients receiving inadequate initial antimicrobial therapy compared with patients receiving adequate initial therapy (24.7% vs 16.2%; p < 0.039). Similarly, Rello et al12Rello 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 (439) Google Scholar found that patients with VAP who received inadequate initial antibiotic therapy had significantly greater crude mortality rates (63.0% vs 41.5%; p = 0.06) and VAP attributable mortality rates (37.0% vs 15.6%; p < 0.05) compared with patients receiving adequate initial antibiotic therapy. Lastly, our own group confirmed these findings in a study employing mini-BAL to obtain lower respiratory tract cultures in patients with suspected VAP.13Kollef MH Ward S The influence of mini-BAL cultures on patient outcomes: implications for the antibiotic management of ventilator associated pneumonia.Chest. 1998; 113: 412-420Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar Table 1 summarizes the pathogens associated with inadequate initial empiric antimicrobial treatment of culture-positive VAP in the four clinical studies noted above.10Luna 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 (817) Google Scholar, 11Alvarez-Lerma F Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit: ICU-Acquired Pneumonia Study Group.Intensive Care Med. 1996; 22: 387-394Crossref PubMed Scopus (589) Google Scholar, 12Rello 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 (439) Google Scholar, 13Kollef MH Ward S The influence of mini-BAL cultures on patient outcomes: implications for the antibiotic management of ventilator associated pneumonia.Chest. 1998; 113: 412-420Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar Most episodes of inadequate antimicrobial treatment were attributed to Gram-negative bacteria, with Pseudomonas aeruginosa, Acinetobacter species, Klebsiella pneumoniae, and Enterobacter species accounting for most cases. These same species of Gram-negative bacteria are often associated with antibiotic resistance and worse patient outcomes compared with more antibiotic susceptible strains of Gram-negative bacteria (eg, Haemophilus influenzae, Escherichia coli).14Fagon JY Chastre J Domart Y et al.Mortality due to ventilator-associated pneumonia or colonization with Psuedomonas or Acinetobacteria species: assessment by quantitative culture of samples obtained by a protected specimen brush.Clin Infect Dis. 1996; 23: 538-542Crossref PubMed Scopus (159) Google Scholar, 15Kollef MH Silver P Murphy DM et al.The effect of late-onset ventilator-associated pneumonia in determining patient mortality.Chest. 1995; 108: 1655-1662Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar Methicillin-resistant Staphylococcus aureus (MRSA) was the next most common pathogen associated with the administration of inadequate antimicrobial treatment. Interestingly, only one of these four studies reported using specific methods for the isolation of anaerobic bacteria.12Rello 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 (439) Google Scholar This probably accounts for the lack of identified anaerobic bacteria in the lower airway cultures from these studies.Table 1Pathogens Associated With Inadequate Initial EmpiricAntimicrobial Treatment of VAPAlvarez-Lerma11Alvarez-Lerma F Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit: ICU-Acquired Pneumonia Study Group.Intensive Care Med. 1996; 22: 387-394Crossref PubMed Scopus (589) Google ScholarKollef and Ward13Kollef MH Ward S The influence of mini-BAL cultures on patient outcomes: implications for the antibiotic management of ventilator associated pneumonia.Chest. 1998; 113: 412-420Abstract Full Text Full Text PDF PubMed Scopus (456) Google ScholarLuna et al10Luna 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 (817) Google ScholarRello et al12Rello 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 (439) Google ScholarCulture-positive patients, No.4306065100Patients receiving inadequate initial treatment, No. (%)146 (34)44 (73)34 (52)27 (27)Pathogens associated with inadequate treatment, No.P aeruginosa6419720S aureus3012*All resistant to methicillin.25†Predominantly resistant to methicillin.3‡One of three resistant to methicillin.Acinetobacter species283270K pneumoniae21130Streptococcus pneumoniae3000H influenzae1001E coli4002Enterobacter species8400Proteus mirabilus4010Serratia marcescens5300Stenotrophomonas maltophilia0500Moraxella morganii0001Candida species0230Viral species0300Streptococcus viridans0020* All resistant to methicillin.† Predominantly resistant to methicillin.‡ One of three resistant to methicillin. Open table in a new tab The clinical importance of not specifically treating anaerobic bacteria in patients with suspected VAP is unknown. In this issue of CHEST Marik and Careau (see page 178) describe their experience with 185 episodes of suspected VAP or aspiration pneumonia (AP) in 143 patients. Despite using specific methods to isolate anaerobic bacteria, only one anaerobic microorganism was isolated from 75 episodes classified as either VAP or AP. These results differ somewhat from those of Dore’ and coworkers16Dore' P Robert R Grollier G et al.Incidence of anaerobes in ventilator-associated pneumonia with use of a protected specimen brush.Am J Respir Crit Care Med. 1996; 153: 1292-1298Crossref PubMed Scopus (112) Google Scholar who examined 130 patients with microbiologically documented VAP using protected specimen brush (PSB) cultures and rigorous anaerobic culturing techniques. Among these patients, 100 (77%) had only aerobic bacterial strains isolated from PSB cultures. In 30 (23%) patients, PSB cultures resulted in anaerobic strains. Aerobic strains were associated with anaerobic strains in 26 patients, whereas 4 patients had only anaerobic strains isolated from PSB cultures. The 3-month mortality rates were reported to be similar for patients with and without anaerobic strains isolated (31% vs 36%). However, the influence of the adequacy of the initially prescribed antimicrobial treatment, for both aerobic and anaerobic bacterial strains isolated from the PSB cultures, on patient outcomes was not described in this investigation. To date, and to our knowledge, no convincing clinical data are available supporting the hypothesis that routine treatment for anaerobic bacteria will improve the outcomes of patients with suspected VAP. Alternatively, several investigations have highlighted the problems associated with the overuse of anaerobic antibiotics, particularly clindamycin, in the hospital setting. These problems include antibiotic-associated diarrhea or colitis due to Clostridium difficile infection, direct end-organ drug toxicity, and unnecessary increases in medical care costs.17Gerding DN Johnson S Peterson LR et al.Clostridium difficile-associated diarrhea and colitis.Infect Control Hosp Epidemiol. 1995; 16: 459-477Crossref PubMed Scopus (567) Google Scholar, 18Climo MW Israel DS Wong ES et al.Hospital-wide restriction of clindamycin: effect on the incidence of Clostridum difficile-associated diarrhea and cost.Ann Intern Med. 1998; 128: 989-995Crossref PubMed Google Scholar What appears to be currently needed are well-performed outcome studies aimed at determining the most effective, least toxic, and most cost-efficient approaches for the initial empiric treatment of suspected VAP. Included within such studies could be an evaluation of the routine administration of specific antimicrobial agents directed against anaerobic bacterial strains. However, as noted by the experience in patients with VAP described above,10Luna 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 (817) Google Scholar, 11Alvarez-Lerma F Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit: ICU-Acquired Pneumonia Study Group.Intensive Care Med. 1996; 22: 387-394Crossref PubMed Scopus (589) Google Scholar, 12Rello 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 (439) Google Scholar, 13Kollef MH Ward S The influence of mini-BAL cultures on patient outcomes: implications for the antibiotic management of ventilator associated pneumonia.Chest. 1998; 113: 412-420Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar developing new strategies aimed at providing improved initial antimicrobial coverage for potentially antibiotic-resistant Gram-negative bacteria and MRSA may yield greater clinical benefits. At the present time, clinicians should be aware of the most common bacterial pathogens, and their antimicrobial resistance patterns, accounting for VAP at the hospitals where they practice. Prescribing an initial broad-spectrum antibiotic regimen to cover all likely pathogens will help to reduce the occurrence of inadequate treatment and may result in improved clinical outcomes. Initial combination antimicrobial therapy, particularly aimed against antibiotic-resistant Gram-negative bacteria (eg, P aeruginosa, Acinetobacter species) and MRSA, offers the greatest likelihood of providing adequate initial treatment. However, such broad-spectrum treatment should not be unnecessarily prolonged unless supported by appropriate culture data in order to avoid the emergence of antibiotic-resistant infections. The selection of the most effective combination of initial antibiotics for the treatment of suspected VAP is unknown at present. Nevertheless, emerging clinical data are becoming available to offer practical suggestions for consideration of what constitutes optimal initial antimicrobial therapy for VAP. One study found that imipenem plus amikacin plus vancomycin was the most effective drug regimen for patients at high risk of developing VAP due to antimicrobial-resistant bacteria.19Trouillet 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 (775) Google Scholar Other combinations of initial empiric antibiotics may also be effective and await identification in future clinical trials. The Role of Anaerobes in Patients With Ventilator-associated Pneumonia and Aspiration Pneumonia: A Prospective StudyCHESTVol. 115Issue 1PreviewAspiration of oropharyngeal material, with its high concentration of anaerobic bacteria, has been implicated in the pathogenesis of both ventilator-associated pneumonia (VAP) and aspiration pneumonitis (AP). Consequently, patients with these disorders are usually treated with antimicrobial agents with anaerobic activity. Full-Text PDF