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Single versus combination antimicrobial therapy for ventilator-associated pneumonia
Single Versus Combination Antimicrobial Therapy for Ventilator-Associated Pneumonia Mark A. Malangoni, MD, Cleveland, Ohio
The appropriate selection of definitive antimicrobial therapy is a necessary component of the overall treatment for ventilator-associated pneumonia. When possible, single-agent therapy is preferable. A combination of antibiotics is necessary to treat multiple organisms not susceptible to a single appropriate antibiotic and when antibiotic-resistant gram-negative bacteria are present. Treatment failure is more commonly the result of persistent pneumonia and the development of antibiotic resistance than to recurrence after successful antimicrobial therapy. The duration of treatment will vary depending on the severity of the underlying illness and the pneumonic process. Am J Surg. 2000;179(Suppl 2A): 58S– 62S. © 2000 by Excerpta Medica, Inc.
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osocomial pneumonia is the second most common hospital-acquired infection in surgical patients. More important, it is the leading cause of death resulting from nosocomial infections. Ventilator-associated pneumonia (VAP) is a particular subset of patients with nosocomial pneumonia who develop a serious infection of the lower respiratory tract while receiving mechanical ventilatory support. In general, this patient group has a greater severity of illness, usually measured by the APACHE II score. These patients also have an increased risk of infection resulting from antibiotic-resistant organisms.1,2 Intubation of the upper airway bypasses important local host defense mechanisms that usually restrict the entry of the bacteria into the lower respiratory tract. When other host defenses are compromised or the bacterial inoculum is overwhelming, infection occurs. VAP presents challenges in recognition, diagnosis, and management. The appropriate use of antibiotics is an important component of management of patients with VAP, and proper antibiotic administration has been demonstrated to improve outcome.3,4 Empiric therapy is begun when the diagnosis is made and often consists of broadspectrum antibiotics that are effective against the suspected pathogens. The choice of antibiotics used should be based on the Gram stain of material from the lower airways, usually sputum or, in some circumstances, a bronchoscopically obtained specimen. When the culture and antibiotic sensitivity results return, the antibiotic choice should be refined to institute directed therapy based on the pathogens isolated on culture.
GOALS OF TREATMENT
From the Department of Surgery, Case Western Reserve University School of Medicine, MetroHealth Medical Center Campus, Cleveland, Ohio, USA. Requests for reprints should be addressed to Mark A. Malangoni, MD, Department of Surgery, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, Ohio 44109-1998.
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© 2000 by Excerpta Medica, Inc. All rights reserved.
The goal of directed antimicrobial therapy is to eradicate effectively the pathogens causing the infection. Secondary goals include minimizing pharmacy expenses, such as the drug costs, as well as preparation and administrative costs; minimizing the use of personnel, both for pharmacy and for nursing; decreasing any adverse effects of drug administration; and reducing pressures for the development of antibiotic resistance in the hospital environment. These goals usually can be accomplished by treatment with a single drug, commonly referred to as monotherapy. Combination therapy is the use of multiple drugs for treatment. It is often needed for the initial empiric treatment of VAP resulting from gram-negative bacteria or mixed gram-positive and gram-negative organisms. After the causative microorganisms have been identified, combination therapy is necessary when multiple organisms are isolated or when VAP is the result of “high-risk” organisms that either are known to be highly resistant to antibiotics or commonly develop antibiotic resistance while on therapy. Patients with VAP will have multiple organisms isolated on culture in approximately 40% to 50% of cases.2,5,6 0002-9610/00/$–see front matter PII S0002-9610(00)00322-6
SINGLE VERSUS COMBINATION ANTIMICROBIAL THERAPY/MALANGONI
Figure 1. The relationship of alveolar oxygen pressure (PAO2) to arterial oxygen pressure (PaO2) for successfully treated patients (dotted line) and for patients who failed treatment (solid line). Bars represent the standard error of the mean. Numbers in parentheses reflect the number of observations. (Reprinted with permission from Am J Surg.2)
It may not be possible to identify a single antibiotic that is effective against multiple pathogens, particularly if methicillin-resistant Staphylococcus aureus is one of the causative organisms. Varying patterns of antibiotic resistance among both gram-positive and gram-negative bacteria, as well as other factors such as medication allergies, also can influence the need for combination antibiotic therapy.
OUTCOME Various parameters influence the outcome of VAP. Although it may be possible to recover from pneumonia in some situations without antibiotic treatment, there is little doubt that antibiotics should be used to treat patients in whom the diagnosis is established. Several reports have demonstrated that appropriate antibiotic therapy for nosocomial pneumonia is associated with a lower mortality.3–5 It also is important to treat all of the pathogens isolated on sputum culture.2,5 Pneumonias resulting from Pseudomonas aeruginosa and S. aureus have been associated with higher rates of treatment failure.2,3,7,8 Malangoni et al2 have demonstrated that a greater alveolar-arterial oxygen gradient on the day of diagnosis as well as a shorter duration of ventilation were associated with failed treatment of VAP in surgical patients (Figure 1). It is possible that these parameters reflect the degree of physiologic derangement or an increased severity of underlying pulmonary disease, both of which intrinsically predict a worse outcome for treatment of VAP. Patients who receive prolonged ventilatory support are more likely to have pneumonia resulting from multiple antibiotic-resistant organisms. Colonization of the airways is a preceding or potentially predisposing event that can eventually result in infection.9 The use of antibiotics earlier in the course of hospitalization has been shown to
increase the risk of pneumonia resulting from multiple antibiotic-resistant bacteria as well as the mortality of this infection.10,11 Patients with pneumonia and associated bacteremia are at a higher risk for mortality.12,13 Bacteremia often indicates a more susceptible host and may represent either an overwhelming of host defense mechanisms by the bacterial inoculum or diminished host defenses resulting from preexisting disease. Regardless of the cause, these patients do not fare as well as those patients without bacteremia, regardless of the pathogen. Other parameters associated with poor outcome in VAP are an increased APACHE II score and the development of organ failure, particularly respiratory failure.4,6,11,14 There is controversy as to whether patients die directly from pneumonia or die instead from other illnesses, with pneumonia occurring either as a terminal event or as an incidental infection that is not life threatening. It is clear that pneumonia can occur in terminally ill patients in whom pneumonia often represents the final event before death. On the other hand, most patients in surgical intensive care units are not terminally ill, and therefore it is prudent to recognize that VAP is an important cause of mortality. Fagon and colleagues have reported that VAP has an attributable mortality of 32%.15 Most important, they demonstrated that patients who had VAP resulting from Pseudomonas and Acinetobacter had a disproportionately greater likelihood of dying compared with patients with pneumonia resulting from other organisms. Pneumonia resulting from these two pathogens, both of which are frequently resistant to multiple antibiotics, was associated with an attributable mortality of 43% compared with only
THE AMERICAN JOURNAL OF SURGERY® VOLUME 179 (Suppl 2A) FEBRUARY 2000
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SINGLE VERSUS COMBINATION ANTIMICROBIAL THERAPY/MALANGONI
TABLE I Indications for Single-Drug Therapy for Ventilator-Associated Pneumonia ● Single organism except for multiple antibiotic-resistant bacteria ● Multiple organisms susceptible to a single antimicrobial drug ● Staphylococcus aureus pneumonia
TABLE II Combination Antibiotic Therapy for Multiple Antibiotic-Resistant Gram-Negative Bacteria Aminoglycoside or ciprofloxacin plus any of the following: ● -lactam/-lactamase inhibitor ● Antipseudomonal penicillin ● Carbapenem ● Aztreonam ● Antipseudomonal third-generation cephalosporin (eg, ceftazidime or cefoperazone) ● Fourth-generation cephalosporin (eg, cefipime)
15% for other bacteria.15 The development of nosocomial pneumonia has been demonstrated to increase the mortality of patients with intra-abdominal infection and also increases the incidence of multiple organ failure.14,16
INDICATIONS FOR MONOTHERAPY Table I shows the current indications for the use of single-drug therapy for the treatment of VAP. Most pneumonias in this category are caused by pathogens that will be susceptible to a second- or third-generation cephalosporin, a -lactam antibiotic combined with a -lactamase inhibitor, or aztreonam. For patients who are allergic to penicillin, a fluoroquinolone can be used. Patients with staphylococcal pneumonia should be treated with either nafcillin (methicillin-sensitive S. aureus) or vancomycin (methicillin-resistant S. aureus). Patients who develop early VAP (within the first 5 days of hospitalization) usually have pneumonia resulting from Haemophilus influenzae, S. pneumoniae, methicillin-sensitive S. aureus, and Enterobacter.17,18 These organisms can be treated effectively with a single drug and have a low incidence of antibiotic resistance, as long as a second- or third-generation cephalosporin is not used to treat Enterobacter.19 Early VAP is frequently the result of a single organism, which enables the use of a single antibiotic.
INDICATIONS FOR COMBINATION ANTIBIOTIC THERAPY The presence of multiple pathogens may require the use of a combination of antibiotics. This situation is common when both gram-positive and gram-negative pathogens are identified. In addition, certain gram-negative bacteria that demonstrate multiple antibiotic resistance also should be treated with combination therapy. These bacteria would include P. aeruginosa, Serratia, Acinetobacter, and some Enterobacter infections.20,21 Although many Enterobacter species are not resistant to multiple antibiotics, resistance can be induced quickly if a second- or third-generation ceph60S
alosporin is chosen for empiric treatment, and therefore combination antibiotic therapy may be needed by the time definitive therapy is begun. When combination therapy is used, drugs that have different mechanisms of bacterial killing should be used in order to minimize the development of resistance while on treatment.20 Acceptable choices for combination antibiotic therapy for the problematic gram-negative bacteria listed above are shown in Table II.
ANTIBIOTIC RESISTANCE Antibiotic resistance can develop by a number of mechanisms. Most -lactam drugs, such as penicillins and cephalosporins, are susceptible to the effects of a variety of -lactamases. Beta-lactamase production can be mediated through either plasmids or chromosomal transfer mechanisms. Other mechanisms of resistance include alterations in penicillin-binding proteins, which reduce the binding affinity of the drug to bacteria and decrease permeability of the bacterial cell wall to the -lactam antibiotic. Antibiotic tolerance is unusual but can occur in gram-positive bacteria. The -lactamases produced by gram-negative bacteria can be categorized in broad enzyme classes and are either constitutively present or inducible. These -lactamases are strategically located in the periplasmic space between the inner and outer membranes of the bacterial cell. Species of Enterobacter, Serratia, and Pseudomonas can also produce large quantities of type I chromosomal -lactamases either because of the selective survival of derepressed mutant strains or because of the reversible induction of enzyme synthesis induced by other -lactam antibiotics (eg, second- or third-generation cephalosporins). These type I -lactamases can bind third-generation cephalosporins with a high degree of affinity and render them inactive. Most important, type I -lactamase–producing bacterial strains are frequently resistant to other cephalosporins, most penicillins, and monobactam antibiotics.
THE AMERICAN JOURNAL OF SURGERY® VOLUME 179 (Suppl 2A) FEBRUARY 2000
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Bacterial resistance to aminoglycosides is primarily caused by plasmid-mediated enzymatic inactivation. These aminoglycoside-inactivating enzymes are usually individualized, and therefore resistance to this class of drug varies widely among hospitals. In addition, decreased uptake of aminoglycosides by certain gram-negative bacteria and alteration of ribosomal binding sites are other means for the development of bacterial resistance to this class of drugs. Resistance to fluoroquinolones generally is caused by chromosomal mutations that alter DNA gyrase or changes in outer membrane proteins that affect bacterial membrane permeability. The development of cross resistance between fluoroquinolones and other classes of antimicrobial agents is uncommon.
PHARMACOKINETICS The concentration of the antimicrobial drug is an important factor that influences its effectiveness. Aminoglycosides have relatively poor penetration into the respiratory tract. In addition to low drug concentrations, aminoglycosides can be inactivated in the acidic environment of the pneumonic lung. For these reasons, an aminoglycoside should not be used alone to treat gram-negative pneumonias. Fluoroquinolones reach a concentration in bronchial secretions that often exceeds serum drug levels. The concentration of most -lactam antibiotics in pulmonary secretions is similar to serum. Beta-lactam antibiotics and vancomycin exhibit timedependent bacterial killing. Therefore, it is important to have a long period of exposure above the minimal inhibitory concentration (MIC) of the antibiotic. Aminoglycosides and fluoroquinolones demonstrate concentration-dependent killing, so it is critical to have a long exposure to high antibiotic concentrations when using these drugs. The fluoroquinolones and aminoglycosides have a prolonged postantibiotic effect (PAE). This property allows these agents to continue to suppress bacterial growth even after the antibiotic concentration falls below the MIC of the pathogen. Beta-lactam antibiotics have a negligible PAE, with the exception of carbapenem antibiotics, which demonstrate a PAE against gram-negative bacilli. The pharmacodynamic parameters influence the dosing of certain antibiotics. The best example of this is the administration of aminoglycosides in a single daily dose, which provides a high peak concentration of antibiotic and takes advantage of its concentration-dependent killing mechanism and long PAE.
DURATION OF THERAPY There are no prospective studies to guide the optimal duration of therapy. It seems intuitive that the duration should be individualized and will depend on the severity of the pneumonic process, the clinical response to treatment, the virulence of the responsible pathogen, and the underlying health of the patient. Defervescence, resolution of leukocytoses, decreased sputum production, and return of normal physiologic function are important indicators of the resolution of pneumonia.22 Chest radiographic findings frequently do not resolve as rapidly as the patient’s well-being improves. When these factors return to normal and a single low-risk pathogen is involved, treatment can be as short as 7 to 10 days. Patients
with antibiotic-resistant organisms, multilobar involvement, cavitation, necrotizing pneumonitis, malnutrition, and serious physiologic derangement often require treatment for 14 days or longer.20 Antibiotics should be given parenterally at the onset of treatment. Once resolution of the pneumonia has begun, an appropriate oral antibiotic can be used provided the organism is susceptible and adequate serum concentrations can be achieved by the oral route. This switch to oral therapy is more convenient for the patient and usually reduces the cost of treatment.
FAILURE OF TREATMENT Treatment failure of VAP in surgical patients can vary widely but generally ranges from 30% to 35%.2– 4,17,18,23 Failure can occur as a result of the development of antibiotic resistance or persistence of the original pathogens. Recurrent pneumonia occurs less commonly than persistence. Recurrent pneumonia is often the result of gramnegative bacteria, and multiple antibiotic-resistant organisms are common.2,22 There are a variety of reasons that treatment failure of VAP can occur. The selection of an empiric antibiotic that does not adequately treat the responsible pathogens may allow the pneumonic process to progress even though the patient is receiving the treatment. In a minority of patients, an unrecognized complication such as a lung abscess or empyema can develop, which usually requires drainage in addition to adequate antimicrobial therapy. Extrapulmonary infections also can occur and can lead to confusion when assessing the effectiveness of antimicrobial therapy for VAP. Persistent infection resulting from antibiotic-resistant organisms generally results in a rapid deterioration in patient condition. In contrast, the development of recurrent pneumonia usually occurs in patients who have had initial improvement. After successful management, these patients have a relapse and often will have an increasing oxygen requirement. Patients who have recovered enough to be extubated may require reintubation for treatment failure.
REFERENCES 1. Kollef MH, Silver P, Murphy DM, Trovillion E. The effect of late-onset ventilator-associated pneumonia in determining patient mortality. Chest. 1995;108:1655–1662. 2. Malangoni MA, Crafton R, Mocek FC. Pneumonia in the surgical intensive unit: factors determining successful outcome. Am J Surg. 1994;167:250 –255. 3. Celis R, Torres A, Gatell JM, et al. Nosocomial pneumonia: a multivariate analysis of risk and prognosis. Chest. 1988;93:318 –324. 4. Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115:462– 474. 5. Mock CN, Burchard KW, Hasan F, Reed M. Surgical intensive care unit pneumonia. Surgery. 1988;104:494 – 499. 6. Fagon JY, Chastre J, Vuagnat A, et al. Nosocomial pneumonia and mortality among patients in intensive care units. JAMA. 1996; 275:866 – 869. 7. Croce MA, Fabian TC, Stewart RM, et al. Empiric monotherapy versus combination therapy of nosocomial pneumonia in trauma patients. J Trauma. 1993;35:303–307. 8. Rello J, Rue M, Jubert P, et al. Survival in patients with nosocomial pneumonia: impact of the severity of illness and the etiologic agent. Crit Care Med. 1997;25:1862–1867. 9. Johanson WG Jr, Pierce AK, Sanford JP, Thomas GD. Nosoco-
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mial respiratory infections with gram-negative bacilli: the significance of colonization of the respiratory tract. Ann Intern Med. 1972;77:701–706. 10. Rello J, Ausina V, Ricart M, Castella J, Prats G. Impact of previous antimicrobial therapy on the etiology and outcome of ventilator-associated pneumonia. Chest. 1993;104:1230 –1235. 11. Kollef MH. Ventilator-associated pneumonia: a multivariate analysis. JAMA. 1993;270:1965–1970. 12. Phair JP, Bassaris HP, Williams JE, Metzger E. Bacteremic pneumonia due to gram-negative bacilli. Arch Intern Med. 1983; 143:2147–2149. 13. Rello J, Torres A, Ricart M, et al. Ventilator-associated pneumonia by Staphylococcus aureus: comparison of methicillin-resistant and methicillin-sensitive episodes. Am J Respir Crit Care Med. 1994;150:1545–1549. 14. Sauaia A, Moore FA, Moore EE, Haenel JB, Read RA. Pneumonia: cause or symptom of postinjury multiple organ failure? Am J Surg. 1993;166:606 – 611. 15. Fagon JY, Chastrert J, Hance AJ, et al. Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay. Am J Med. 1993;94:281–299. 16. Mustard RA, Bohnen JMA, Rosati C, Schouten BD. Pneumonia complicating abdominal sepsis: an independent risk factor for mortality. Arch Surg. 1992;126:170 –175.
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17. Polk HC Jr, Livingston DL, Fry DE, et al. Treatment of pneumonia in mechanically ventilated trauma patients: results of a prospective trial. Arch Surg. 1997;132:1086 –1092. 18. Polk HC Jr, Heinzelmann M, Mercer-Jones MA, Malangoni MA, Cheadle WG. Pneumonia in the surgical patient. Curr Prob Surg. 1997;34:117–208. 19. Chow JW, Fine MJ, Schlaes DM, et al. Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy. Ann Intern Med. 1991;115:585–590. 20. American Thoracic Society. Hospital-acquired pneumonia in adults: diagnosis, assessment of severity, initial antimicrobial therapy, and preventative strategies. Am J Respir Crit Care Med. 1995; 153:1711–1725. 21. Hilf M, Yu VL, Sharp J, et al. Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients. Am J Med. 1989;67:540 –546. 22. Wunderink RG. Ventilator-associated pneumonia: failure to respond to antibiotic therapy. Clin Chest Med. 1995;16:173–193. 23. Fink 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 Agent Chemother. 1994;38: 547–557.
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The appropriate selection of definitive antimicrobial therapy is a necessary component of the overall treatment for ventilator-associated pneumonia. When possible, single-agent therapy is preferable. A combination of antibiotics is necessary to treat multiple organisms not susceptible to a single appropriate antibiotic and when antibiotic-resistant gram-negative bacteria are present. Treatment failure is more commonly the result of persistent pneumonia and the development of antibiotic resistance than to recurrence after successful antimicrobial therapy. The duration of treatment will vary depending on the severity of the underlying illness and the pneumonic process. Am J Surg. 2000;179(Suppl 2A): 58S– 62S. © 2000 by Excerpta Medica, Inc.
N
osocomial pneumonia is the second most common hospital-acquired infection in surgical patients. More important, it is the leading cause of death resulting from nosocomial infections. Ventilator-associated pneumonia (VAP) is a particular subset of patients with nosocomial pneumonia who develop a serious infection of the lower respiratory tract while receiving mechanical ventilatory support. In general, this patient group has a greater severity of illness, usually measured by the APACHE II score. These patients also have an increased risk of infection resulting from antibiotic-resistant organisms.1,2 Intubation of the upper airway bypasses important local host defense mechanisms that usually restrict the entry of the bacteria into the lower respiratory tract. When other host defenses are compromised or the bacterial inoculum is overwhelming, infection occurs. VAP presents challenges in recognition, diagnosis, and management. The appropriate use of antibiotics is an important component of management of patients with VAP, and proper antibiotic administration has been demonstrated to improve outcome.3,4 Empiric therapy is begun when the diagnosis is made and often consists of broadspectrum antibiotics that are effective against the suspected pathogens. The choice of antibiotics used should be based on the Gram stain of material from the lower airways, usually sputum or, in some circumstances, a bronchoscopically obtained specimen. When the culture and antibiotic sensitivity results return, the antibiotic choice should be refined to institute directed therapy based on the pathogens isolated on culture.
GOALS OF TREATMENT
From the Department of Surgery, Case Western Reserve University School of Medicine, MetroHealth Medical Center Campus, Cleveland, Ohio, USA. Requests for reprints should be addressed to Mark A. Malangoni, MD, Department of Surgery, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, Ohio 44109-1998.
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© 2000 by Excerpta Medica, Inc. All rights reserved.
The goal of directed antimicrobial therapy is to eradicate effectively the pathogens causing the infection. Secondary goals include minimizing pharmacy expenses, such as the drug costs, as well as preparation and administrative costs; minimizing the use of personnel, both for pharmacy and for nursing; decreasing any adverse effects of drug administration; and reducing pressures for the development of antibiotic resistance in the hospital environment. These goals usually can be accomplished by treatment with a single drug, commonly referred to as monotherapy. Combination therapy is the use of multiple drugs for treatment. It is often needed for the initial empiric treatment of VAP resulting from gram-negative bacteria or mixed gram-positive and gram-negative organisms. After the causative microorganisms have been identified, combination therapy is necessary when multiple organisms are isolated or when VAP is the result of “high-risk” organisms that either are known to be highly resistant to antibiotics or commonly develop antibiotic resistance while on therapy. Patients with VAP will have multiple organisms isolated on culture in approximately 40% to 50% of cases.2,5,6 0002-9610/00/$–see front matter PII S0002-9610(00)00322-6
SINGLE VERSUS COMBINATION ANTIMICROBIAL THERAPY/MALANGONI
Figure 1. The relationship of alveolar oxygen pressure (PAO2) to arterial oxygen pressure (PaO2) for successfully treated patients (dotted line) and for patients who failed treatment (solid line). Bars represent the standard error of the mean. Numbers in parentheses reflect the number of observations. (Reprinted with permission from Am J Surg.2)
It may not be possible to identify a single antibiotic that is effective against multiple pathogens, particularly if methicillin-resistant Staphylococcus aureus is one of the causative organisms. Varying patterns of antibiotic resistance among both gram-positive and gram-negative bacteria, as well as other factors such as medication allergies, also can influence the need for combination antibiotic therapy.
OUTCOME Various parameters influence the outcome of VAP. Although it may be possible to recover from pneumonia in some situations without antibiotic treatment, there is little doubt that antibiotics should be used to treat patients in whom the diagnosis is established. Several reports have demonstrated that appropriate antibiotic therapy for nosocomial pneumonia is associated with a lower mortality.3–5 It also is important to treat all of the pathogens isolated on sputum culture.2,5 Pneumonias resulting from Pseudomonas aeruginosa and S. aureus have been associated with higher rates of treatment failure.2,3,7,8 Malangoni et al2 have demonstrated that a greater alveolar-arterial oxygen gradient on the day of diagnosis as well as a shorter duration of ventilation were associated with failed treatment of VAP in surgical patients (Figure 1). It is possible that these parameters reflect the degree of physiologic derangement or an increased severity of underlying pulmonary disease, both of which intrinsically predict a worse outcome for treatment of VAP. Patients who receive prolonged ventilatory support are more likely to have pneumonia resulting from multiple antibiotic-resistant organisms. Colonization of the airways is a preceding or potentially predisposing event that can eventually result in infection.9 The use of antibiotics earlier in the course of hospitalization has been shown to
increase the risk of pneumonia resulting from multiple antibiotic-resistant bacteria as well as the mortality of this infection.10,11 Patients with pneumonia and associated bacteremia are at a higher risk for mortality.12,13 Bacteremia often indicates a more susceptible host and may represent either an overwhelming of host defense mechanisms by the bacterial inoculum or diminished host defenses resulting from preexisting disease. Regardless of the cause, these patients do not fare as well as those patients without bacteremia, regardless of the pathogen. Other parameters associated with poor outcome in VAP are an increased APACHE II score and the development of organ failure, particularly respiratory failure.4,6,11,14 There is controversy as to whether patients die directly from pneumonia or die instead from other illnesses, with pneumonia occurring either as a terminal event or as an incidental infection that is not life threatening. It is clear that pneumonia can occur in terminally ill patients in whom pneumonia often represents the final event before death. On the other hand, most patients in surgical intensive care units are not terminally ill, and therefore it is prudent to recognize that VAP is an important cause of mortality. Fagon and colleagues have reported that VAP has an attributable mortality of 32%.15 Most important, they demonstrated that patients who had VAP resulting from Pseudomonas and Acinetobacter had a disproportionately greater likelihood of dying compared with patients with pneumonia resulting from other organisms. Pneumonia resulting from these two pathogens, both of which are frequently resistant to multiple antibiotics, was associated with an attributable mortality of 43% compared with only
THE AMERICAN JOURNAL OF SURGERY® VOLUME 179 (Suppl 2A) FEBRUARY 2000
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SINGLE VERSUS COMBINATION ANTIMICROBIAL THERAPY/MALANGONI
TABLE I Indications for Single-Drug Therapy for Ventilator-Associated Pneumonia ● Single organism except for multiple antibiotic-resistant bacteria ● Multiple organisms susceptible to a single antimicrobial drug ● Staphylococcus aureus pneumonia
TABLE II Combination Antibiotic Therapy for Multiple Antibiotic-Resistant Gram-Negative Bacteria Aminoglycoside or ciprofloxacin plus any of the following: ● -lactam/-lactamase inhibitor ● Antipseudomonal penicillin ● Carbapenem ● Aztreonam ● Antipseudomonal third-generation cephalosporin (eg, ceftazidime or cefoperazone) ● Fourth-generation cephalosporin (eg, cefipime)
15% for other bacteria.15 The development of nosocomial pneumonia has been demonstrated to increase the mortality of patients with intra-abdominal infection and also increases the incidence of multiple organ failure.14,16
INDICATIONS FOR MONOTHERAPY Table I shows the current indications for the use of single-drug therapy for the treatment of VAP. Most pneumonias in this category are caused by pathogens that will be susceptible to a second- or third-generation cephalosporin, a -lactam antibiotic combined with a -lactamase inhibitor, or aztreonam. For patients who are allergic to penicillin, a fluoroquinolone can be used. Patients with staphylococcal pneumonia should be treated with either nafcillin (methicillin-sensitive S. aureus) or vancomycin (methicillin-resistant S. aureus). Patients who develop early VAP (within the first 5 days of hospitalization) usually have pneumonia resulting from Haemophilus influenzae, S. pneumoniae, methicillin-sensitive S. aureus, and Enterobacter.17,18 These organisms can be treated effectively with a single drug and have a low incidence of antibiotic resistance, as long as a second- or third-generation cephalosporin is not used to treat Enterobacter.19 Early VAP is frequently the result of a single organism, which enables the use of a single antibiotic.
INDICATIONS FOR COMBINATION ANTIBIOTIC THERAPY The presence of multiple pathogens may require the use of a combination of antibiotics. This situation is common when both gram-positive and gram-negative pathogens are identified. In addition, certain gram-negative bacteria that demonstrate multiple antibiotic resistance also should be treated with combination therapy. These bacteria would include P. aeruginosa, Serratia, Acinetobacter, and some Enterobacter infections.20,21 Although many Enterobacter species are not resistant to multiple antibiotics, resistance can be induced quickly if a second- or third-generation ceph60S
alosporin is chosen for empiric treatment, and therefore combination antibiotic therapy may be needed by the time definitive therapy is begun. When combination therapy is used, drugs that have different mechanisms of bacterial killing should be used in order to minimize the development of resistance while on treatment.20 Acceptable choices for combination antibiotic therapy for the problematic gram-negative bacteria listed above are shown in Table II.
ANTIBIOTIC RESISTANCE Antibiotic resistance can develop by a number of mechanisms. Most -lactam drugs, such as penicillins and cephalosporins, are susceptible to the effects of a variety of -lactamases. Beta-lactamase production can be mediated through either plasmids or chromosomal transfer mechanisms. Other mechanisms of resistance include alterations in penicillin-binding proteins, which reduce the binding affinity of the drug to bacteria and decrease permeability of the bacterial cell wall to the -lactam antibiotic. Antibiotic tolerance is unusual but can occur in gram-positive bacteria. The -lactamases produced by gram-negative bacteria can be categorized in broad enzyme classes and are either constitutively present or inducible. These -lactamases are strategically located in the periplasmic space between the inner and outer membranes of the bacterial cell. Species of Enterobacter, Serratia, and Pseudomonas can also produce large quantities of type I chromosomal -lactamases either because of the selective survival of derepressed mutant strains or because of the reversible induction of enzyme synthesis induced by other -lactam antibiotics (eg, second- or third-generation cephalosporins). These type I -lactamases can bind third-generation cephalosporins with a high degree of affinity and render them inactive. Most important, type I -lactamase–producing bacterial strains are frequently resistant to other cephalosporins, most penicillins, and monobactam antibiotics.
THE AMERICAN JOURNAL OF SURGERY® VOLUME 179 (Suppl 2A) FEBRUARY 2000
SINGLE VERSUS COMBINATION ANTIMICROBIAL THERAPY/MALANGONI
Bacterial resistance to aminoglycosides is primarily caused by plasmid-mediated enzymatic inactivation. These aminoglycoside-inactivating enzymes are usually individualized, and therefore resistance to this class of drug varies widely among hospitals. In addition, decreased uptake of aminoglycosides by certain gram-negative bacteria and alteration of ribosomal binding sites are other means for the development of bacterial resistance to this class of drugs. Resistance to fluoroquinolones generally is caused by chromosomal mutations that alter DNA gyrase or changes in outer membrane proteins that affect bacterial membrane permeability. The development of cross resistance between fluoroquinolones and other classes of antimicrobial agents is uncommon.
PHARMACOKINETICS The concentration of the antimicrobial drug is an important factor that influences its effectiveness. Aminoglycosides have relatively poor penetration into the respiratory tract. In addition to low drug concentrations, aminoglycosides can be inactivated in the acidic environment of the pneumonic lung. For these reasons, an aminoglycoside should not be used alone to treat gram-negative pneumonias. Fluoroquinolones reach a concentration in bronchial secretions that often exceeds serum drug levels. The concentration of most -lactam antibiotics in pulmonary secretions is similar to serum. Beta-lactam antibiotics and vancomycin exhibit timedependent bacterial killing. Therefore, it is important to have a long period of exposure above the minimal inhibitory concentration (MIC) of the antibiotic. Aminoglycosides and fluoroquinolones demonstrate concentration-dependent killing, so it is critical to have a long exposure to high antibiotic concentrations when using these drugs. The fluoroquinolones and aminoglycosides have a prolonged postantibiotic effect (PAE). This property allows these agents to continue to suppress bacterial growth even after the antibiotic concentration falls below the MIC of the pathogen. Beta-lactam antibiotics have a negligible PAE, with the exception of carbapenem antibiotics, which demonstrate a PAE against gram-negative bacilli. The pharmacodynamic parameters influence the dosing of certain antibiotics. The best example of this is the administration of aminoglycosides in a single daily dose, which provides a high peak concentration of antibiotic and takes advantage of its concentration-dependent killing mechanism and long PAE.
DURATION OF THERAPY There are no prospective studies to guide the optimal duration of therapy. It seems intuitive that the duration should be individualized and will depend on the severity of the pneumonic process, the clinical response to treatment, the virulence of the responsible pathogen, and the underlying health of the patient. Defervescence, resolution of leukocytoses, decreased sputum production, and return of normal physiologic function are important indicators of the resolution of pneumonia.22 Chest radiographic findings frequently do not resolve as rapidly as the patient’s well-being improves. When these factors return to normal and a single low-risk pathogen is involved, treatment can be as short as 7 to 10 days. Patients
with antibiotic-resistant organisms, multilobar involvement, cavitation, necrotizing pneumonitis, malnutrition, and serious physiologic derangement often require treatment for 14 days or longer.20 Antibiotics should be given parenterally at the onset of treatment. Once resolution of the pneumonia has begun, an appropriate oral antibiotic can be used provided the organism is susceptible and adequate serum concentrations can be achieved by the oral route. This switch to oral therapy is more convenient for the patient and usually reduces the cost of treatment.
FAILURE OF TREATMENT Treatment failure of VAP in surgical patients can vary widely but generally ranges from 30% to 35%.2– 4,17,18,23 Failure can occur as a result of the development of antibiotic resistance or persistence of the original pathogens. Recurrent pneumonia occurs less commonly than persistence. Recurrent pneumonia is often the result of gramnegative bacteria, and multiple antibiotic-resistant organisms are common.2,22 There are a variety of reasons that treatment failure of VAP can occur. The selection of an empiric antibiotic that does not adequately treat the responsible pathogens may allow the pneumonic process to progress even though the patient is receiving the treatment. In a minority of patients, an unrecognized complication such as a lung abscess or empyema can develop, which usually requires drainage in addition to adequate antimicrobial therapy. Extrapulmonary infections also can occur and can lead to confusion when assessing the effectiveness of antimicrobial therapy for VAP. Persistent infection resulting from antibiotic-resistant organisms generally results in a rapid deterioration in patient condition. In contrast, the development of recurrent pneumonia usually occurs in patients who have had initial improvement. After successful management, these patients have a relapse and often will have an increasing oxygen requirement. Patients who have recovered enough to be extubated may require reintubation for treatment failure.
REFERENCES 1. Kollef MH, Silver P, Murphy DM, Trovillion E. The effect of late-onset ventilator-associated pneumonia in determining patient mortality. Chest. 1995;108:1655–1662. 2. Malangoni MA, Crafton R, Mocek FC. Pneumonia in the surgical intensive unit: factors determining successful outcome. Am J Surg. 1994;167:250 –255. 3. Celis R, Torres A, Gatell JM, et al. Nosocomial pneumonia: a multivariate analysis of risk and prognosis. Chest. 1988;93:318 –324. 4. Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115:462– 474. 5. Mock CN, Burchard KW, Hasan F, Reed M. Surgical intensive care unit pneumonia. Surgery. 1988;104:494 – 499. 6. Fagon JY, Chastre J, Vuagnat A, et al. Nosocomial pneumonia and mortality among patients in intensive care units. JAMA. 1996; 275:866 – 869. 7. Croce MA, Fabian TC, Stewart RM, et al. Empiric monotherapy versus combination therapy of nosocomial pneumonia in trauma patients. J Trauma. 1993;35:303–307. 8. Rello J, Rue M, Jubert P, et al. Survival in patients with nosocomial pneumonia: impact of the severity of illness and the etiologic agent. Crit Care Med. 1997;25:1862–1867. 9. Johanson WG Jr, Pierce AK, Sanford JP, Thomas GD. Nosoco-
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mial respiratory infections with gram-negative bacilli: the significance of colonization of the respiratory tract. Ann Intern Med. 1972;77:701–706. 10. Rello J, Ausina V, Ricart M, Castella J, Prats G. Impact of previous antimicrobial therapy on the etiology and outcome of ventilator-associated pneumonia. Chest. 1993;104:1230 –1235. 11. Kollef MH. Ventilator-associated pneumonia: a multivariate analysis. JAMA. 1993;270:1965–1970. 12. Phair JP, Bassaris HP, Williams JE, Metzger E. Bacteremic pneumonia due to gram-negative bacilli. Arch Intern Med. 1983; 143:2147–2149. 13. Rello J, Torres A, Ricart M, et al. Ventilator-associated pneumonia by Staphylococcus aureus: comparison of methicillin-resistant and methicillin-sensitive episodes. Am J Respir Crit Care Med. 1994;150:1545–1549. 14. Sauaia A, Moore FA, Moore EE, Haenel JB, Read RA. Pneumonia: cause or symptom of postinjury multiple organ failure? Am J Surg. 1993;166:606 – 611. 15. Fagon JY, Chastrert J, Hance AJ, et al. Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay. Am J Med. 1993;94:281–299. 16. Mustard RA, Bohnen JMA, Rosati C, Schouten BD. Pneumonia complicating abdominal sepsis: an independent risk factor for mortality. Arch Surg. 1992;126:170 –175.
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17. Polk HC Jr, Livingston DL, Fry DE, et al. Treatment of pneumonia in mechanically ventilated trauma patients: results of a prospective trial. Arch Surg. 1997;132:1086 –1092. 18. Polk HC Jr, Heinzelmann M, Mercer-Jones MA, Malangoni MA, Cheadle WG. Pneumonia in the surgical patient. Curr Prob Surg. 1997;34:117–208. 19. Chow JW, Fine MJ, Schlaes DM, et al. Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy. Ann Intern Med. 1991;115:585–590. 20. American Thoracic Society. Hospital-acquired pneumonia in adults: diagnosis, assessment of severity, initial antimicrobial therapy, and preventative strategies. Am J Respir Crit Care Med. 1995; 153:1711–1725. 21. Hilf M, Yu VL, Sharp J, et al. Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients. Am J Med. 1989;67:540 –546. 22. Wunderink RG. Ventilator-associated pneumonia: failure to respond to antibiotic therapy. Clin Chest Med. 1995;16:173–193. 23. Fink 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 Agent Chemother. 1994;38: 547–557.
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