Nosocomial pneumonia guidelines: an international perspective – Disease Management of Pulmonary Infections

Lionel A. Mandell

Hospital-acquired pneumonia is a serious illness with substantial morbidity and mortality. Management of this illness is challenging for the physician and a number of diverse issues must be considered when initiating therapy. Guidelines for the treatment of hospital-acquired pneumonia have been developed in Canada and the United States. A questionnaire sent to infectious disease physicians or clinical microbiologists in 29 countries showed that Australia, Sweden, and France had national guidelines in addition to Canada and the United States, while Hong Kong and France had single hospital-based guidelines. These guidelines are reviewed and some of the controversial issues relating to nosocomial pneumonia are discussed.

(CHEST 1998; 113:188S-193S)

Nosocomial pneumonia is a serious infection with considerable morbidity and mortality. It is the second most common nosocomial infection, but the infection most frequently associated with a fatal outcome.[1,2] The annual incidence is 5 to 10 cases per 1,000 admissions, but this can increase up to 20-fold in ventilated patients.[1,3] Crude mortality rates of up to 70% have been reported, but the more accurate indication of risk of dying is the attributable mortality. These figures run as high as 33 to 50%.[4,5]

The pathogenesis of nosocomial pneumonia is driven largely by the microaspiration or silent aspiration of oropharyngeal flora. Studies in normal individuals have shown that even without a reduced level of consciousness, impaired swallowing mechanism, or gag reflex, normal individuals will aspirate a small amount of oropharyngeal secretions during sleep.[6] The fact that there are no untoward consequences to this is because in healthy individuals, the oropharyngeal flora is made up of relatively benign commensal organisms. However, in the presence of illness or trauma, the oropharyngeal flora shifts quite quickly and dramatically to Gram-negative bacilli. This is as a result of the loss of oropharyngeal cell surface fibronectin that exposes receptors for Gram-negative rods, usually covered in healthy adults by fibronectin.[7,8] The silent aspiration of pathogens such as Klebsiella species or Escherichia coli may well result in pneumonia, particularly if the patient is in any way debilitated.

One study of the microbiology of hospital-acquired pneumonia indicated that in at least 50% of cases, more than one pathogen may be found.[9] To further complicate matters, even when aggressive diagnostic workups are performed, one may not find an etiologic agent in approximately half the cases.

The seriousness of nosocomial pneumonia and the varied and polymicrobial nature of the etiologic agents coupled with the diagnostic problems led to the development of guidelines for initial empiric treatment of nosocomial pneumonia in Canada in 1993.[10] The American Thoracic Society (ATS) followed suit shortly thereafter.[5] To date, we are aware of national level guidelines in four countries, and hospital-based guidelines in two countries. The purpose of this article is to compare and contrast guidelines from various countries that deal with nosocomial pneumonia and to address selected controversial issues of relevance to this disease entity.

MATERIALS AND METHODS

A questionnaire was sent to infectious disease physicians or clinical microbiologists in 29 countries. They were asked if guidelines for nosocomial pneumonia were available in their country and if so, whether they were developed for use in a particular hospital or were national in scope.

When we had received the responses, we compared the guidelines according to the following headings: (1) how the patients were categorized, or the “approach” used; (2) the “pathogens” that were believed to be of concern; and (3) the recommended treatment regimens or “drugs.”

RESULTS AND DISCUSSION

The countries are listed in Table 1 and we can see that of the 29 countries listed, only Australia, Canada, the United States, Sweden, France, and Hong Kong have guidelines. Those from the first four countries mentioned above are national or at least broad based (Sweden) in their approach. Those from France and Hong Kong are single hospital-based guidelines.

Approach

Table 2 lists the various approaches used in the six countries. When the Canadian guidelines were being developed, it was believed that given the problems inherent in the diagnosis of pneumonia and in the determination of an etiologic pathogen, an approach to initial empiric treatment must take into account those factors that are most likely to impact on clinical outcome. Risk factors for pneumonia and for specific pathogens as well as the severity of illness at the time of presentation were believed to be the most important variables.[10]

Table 2–Approach

Country and Approach

Canada

Mild to moderate–no unusual risk factors

Mild to moderate–risk factors

Severe

United States

Mild to moderate–no unusual risk factors, onset anytime

OR severe with early onset

Mild to moderate–risk factors

Severe

Australia

Mild to moderate–no specific risk factors

Mild to moderate–specific risk factors

Severe pneumonia

Sweden

Patients treated at medical institutions with homelike conditions

Patients hospitalized in acute somatic departments

Postoperative patients

France–VAP(*) only

Early onset–no prior antibiotics

Early onset–prior antibiotics

OR

Late onset–no prior antibiotics

Late onset–prior antibiotics

Hong Kong

Mildly ill

Moderately/severely ill

Aspiration

Patients in ICU

(*) VAP = ventilator-associated pneumonia.

In the ATS guidelines, the time of onset of pneumonia was introduced as a third variable.[5] This was based on the fact that studies had suggested that organisms such as Streptococcus pneumoniae and Haemophilus influenzae may be responsible even in severe cases that occur in the first 5 days of hospitalization.[11,12] The Australian and Hong Kong guidelines have relied on risk factors and severity of illness as well; however, the Swedish group has put more emphasis on the location in the hospital where the infection was acquired.

The French guidelines deal only with ventilator-associated pneumonia so that severity is, in fact, implicit in their approach. The specific categories depend primarily on early or late onset of the infection and whether antibiotics have been given. They are, in effect, utilizing an approach based on seventy, risk factors, and time of onset.

Pathogens

The various pathogens that were believed to be important are listed in Table 3. When the Canadian guidelines were developed, it was believed that given the uncertainties and vagaries of diagnosis, one should at least provide antimicrobial coverage directed against a minimum number of key pathogens. Accordingly, the concept of “core” pathogens was developed. In those with mild-to-moderate infections, the core group consists of the enterobacteriaceae and Staphylococcus aureus. If specific risk factors for certain pathogens are present, then such organisms must be considered as well. For example, in those patients who have experienced a gross aspiration event, anaerobes may be important, and those patients receiving high-dose steroids are at risk of infection with Legionella species.

Table 3–Pathogens(*)

Country Pathogens

Canada

Mild-mod Core:

Enterobacteriaceae

+

S aureus

Mild-mod and risk factors Anaerobes

MRSA

Resistant GNR or P aeruginosa

Legionella

Severe Core + P aeruginosa

Legionella

United States

Mild-mod Core

Enterobacteriaceae

S aureus

S pneumoniae

H influenzae

Mild-mod and risk factors Anaerobes

MRSA

P aeruginosa

Legionella,

Severe Core+ P aeruginosa

Acinetobacter

Australia

Mild-mod Core

Klebsiella and other GNRs

S aureus

S pneumoniae

H influenzae

Mild-mod and risk factors Anaerobes

MRSA

Resistant GNR or P aeruginosa

Severe Core+ P aeruginosa

Legionella

Sweden

Medical institutions with S pneumoniae

homelike conditions M pneumoniae

Acute somatic departments Enterobacteriaceae

Postoperative Enterobacteriaceae

ICU Gram-positive bacteria

Enterobacteriaceae

P aeruginosa

Legionella

France

Early onset Enterobacteriaceae

No prior antibiotics +

S aureus

S pneumoniae

H influenzae

Early onset Multidrug-resistant GNR

Prior antibiotics or P aeruginosa

Late onset, no prior

antibiotics Stenotrophomonas maltophilia

Late onset Multidrug resist GNR

Prior antibiotics Multidrug-resistant P aeruginosa

and

Acinetobacter sp

S maltophilia

MRSA

Hong Kong

Mildly ill Gram-negative rods

S aureus

Moderately/severe Gram-negative rods

including Pseudomonas

Enterobacter

Serratia

Aspiration Gram-negative rods

S aureus

anaerobes

(*) GNR = Enterobacteriaceae; MRSA = methicillin-resistant S aureus; mild-mod = mild to moderate.

In those with severe hospital-acquired pneumonia, the Canadian document stipulated that not only must the core pathogens be treated but coverage must also be provided for Pseudomonas aeruginosa and Legionella.[10] The ATS extended this somewhat by adding S pneumoniae and H influenzae to the core group and in the severe group, substituted Acinetobacter for Legionella.[5]

The microorganisms listed in the Australian guidelines are a blend of the Canadian and ATS pathogens as are pathogens given in the Swedish, French, and Hong Kong guidelines.

The list of pathogens in the French guidelines is a bit more extensive but may reflect the microbial epidemiology in the particular hospital for which the guidelines were developed.

Drugs

Given the various pathogens that are listed, the drugs suggested for initial empiric treatment are not at all surprising (Table 4). One obvious pattern that emerges is that of monotherapy vs combination therapy. A combination of drugs is uniformly suggested for severe pneumonia or for pneumonia associated with certain risk factors. In the former case, it is usual to provide extended coverage for a wide variety of pathogens as well as double coverage against P aeruginosa.[13] it is hoped that the combination of drugs will provide additive or possibly synergistic activity against P aeruginosa. In cases of pneumonia associated with risk factors for a specific pathogen, combination treatment is usually given to provide broader coverage.

Table 4-Drug(*)

Country Drug

Canada

Mild-mod IV-cefaz/genta PO-amox/clav

-2nd-gen ceph -2nd gen ceph

-nonpseudo, 3rd- -TMP/SMX

gen ceph -quinolone

Mild-mod with Anaerobes–clinda

risk factors or

BL/BLI

MRSA–vancomycin

Legionella–macrolide

Severe Piperacillin

Ceftazidime

Imipenem+AG

BL/BLI

Ciprofloxacin

United States

Mild-mod or 2nd-gen ceph

early severe Nonpseudo, 3rd-gen ceph

BL/BLI

Risk factors Anaerobes–clinda

or

BL/BLI

MRSA–vancomycin

Severe Legionella–macrolide

Piperacillin

Ceftazidime

Imipenem+AG or

ciprofloxacin

BL/BLI

Australia Aztreonam

Mild-mod Nonpseudo, 3rd-gen ceph

Risk factors Anaerobes–clinda.

or

BL/BLI

MRSA–vancomycin

Legionella–macrolide

Severe AG+erythromycin

+

ceftaz or BL/BLI

France

Early onset BL/BLI

No prior

antibiotics 2nd-gen ceph

Nonpseudo 3rd-gen ceph

Early onset, prior BL/BLI

antibiotics or

late onset Ceftazidime

No prior antibiotic Cefoperazone+AG

or ciprofloxacin

Cefepime

Cefpirome

Imipenem

Late onset AG or ciprofloxacin

Prior antibiotics +

imipenem

+

vancomycin

Sweden

Medical institution Penicillin V

with homelike or

conditions erythromycin

Acute somatic severe–2nd-gen ceph

department or

nonpseudo 3rd-gen ceph

Postoperative 2nd-gen ceph

or

nonpseudo 3rd-gen ceph

ICU Ceftazidime or imipenem or AG

+

piperacillin or cefotaxime or ceftazidime

Hong Kong

Mildly ill 2nd-gen ceph

Moderate/severe 3rd-gen ceph+AG

Aspiration BL/BLI

or

AG+pen G or clinda

or

cefoxitin

(*) BL/BLI = [Beta]-lactam/[Beta]-lactamase inhibitor. See Table 3 footnote for other expansions of abbreviations. Cefaz = cefazolin; gen = generation; genta = gentamicin; ceph = cephalosporin; TMP SMX = trimethoprimsulfamethoxazole; clinda = clindamycin; AG = aminoglycoside; nonpseudo = nonpseudomonas; ceftaz = ceftazidime; po = oral.

Controversies

Despite the introduction of guidelines for the treatment of nosocomial pneumonia, numerous controversies persist. Many of these controversies were highlighted in the ATS statement on the treatment of hospital-acquired pneumonia, and space constraints do not permit a full discussion of each, still several important controversies will be highlighted herein.[5]

Use of quantitative invasive diagnostic procedures (ie, fiberoptic bronchoscopy employing either the protected specimen brush and/or BAL) to retrieve lower respiratory tract secretions in the initial workup of patients with suspected nosocomial pneumonia remains an important area of controversy.[14,15] Those advocating its use note that many different processes, including those that are noninfectious, may present with a picture clinically indistinguishable from pneumonia. They argue that by knowing the etiology, the physician can prescribe specific therapy. Limiting the use of antibiotics is appealing since this would reduce costs, lower the risk of antibiotic-related adverse events, and decrease the selective pressure of antibiotics that, may increase microbial resistance. Some argue that use of invasive diagnostic testing in the setting of nosocomial pneumonia is, itself, cost effective. However, no diagnostic approach is without problems, and with invasive diagnostic procedures such as fiberoptic bronchoscopy, questions remain as to who should be tested, how frequently invasive procedures should be performed, as well as the accuracy of the invasive diagnostic procedures. Additionally, such procedures require a competent operator who appreciates the limitations of such testing, the ability and resources to perform quantitative bacterial cultures, and sufficient confidence in the procedure to warrant withholding of antibiotics when the results for invasive diagnostic testing suggest that pneumonia is not present. Finally, it should be stated that to date, no studies have shown that incorporating these procedures in the management of nosocomial pneumonia affects the patient’s outcome.

Another controversy centers around the appropriate treatment of patients with pneumonia caused by drug-resistant S pneumoniae. S pneumoniae remains an important pathogen in patients with nosocomial pneumonia especially early in the hospital course. In recent years, S pneumoniae has become increasingly resistant to penicillin, other [Beta]-lactam agents, and other classes of antibiotics. Since initial therapy for pneumonia is started without knowing the exact pathogen, in areas where drug-resistant S pneumoniae is common, the question frequently arises as to what is appropriate empiric therapy. Reports to date suggest that the occurrence of penicillin resistance not only varies dramatically from one location to another, but from hospital to hospital within the same geographic area.[16] Penicillin resistance often develops abruptly in a community and once present the incidence increases rapidly. In some countries, the incidence of penicillin-resistant S pneumoniae is reported to be in excess of 40%. Penicillin resistance results from multiple and apparently stable mutations of penicillin binding proteins, but does not appear to affect virulence. Resistance to penicillin is categorized as either intermediate (minimum inhibitory concentration [MIC], 0.1 to 1 [micro]g/mL) or high (MIC [is greater than or equal to] 2.0 [micro]g/mL). Since these levels were chosen with the treatment of pneumococcal meningitis in mind, the significance of intermediate penicillin resistance in cases of pneumonia is probably not of therapeutic importance. S pneumoniae resistance to other antimicrobial agents appears to parallel the increasing incidence of resistance to penicillin.

In a retrospective study of 24 patients, risk factors for infection with a resistant strain of pneumococcus were determined. They were use of [Beta]-lactam antibiotics or hospitalization during the previous 3 months, nosocomial pneumonia, episodes of pneumonia during the previous year, and an initially critical condition on presentation.[17] A prospective study of 374 patients showed a statistically significant association between infection with resistant pneumococci and age of 0 to 4 years, an immunosuppressive underlying disease, and prior use of [Beta]-lactam antibiotics.[18]

Pallares et al[19] suggest that in those without risk factors associated with dying or infection with a resistant pathogen, high-dose IV penicillin G, ampicillin, or amoxicillin may be used, whereas in those with such risk factors present, ceftriaxone or cefotaxime should be given. In the event that cephalosporin resistance increases, with MICs reaching [is greater than or equal to] 4 [micro]g/mL, it is not known whether a third-generation cephalosporin would still be appropriate and consideration should be given to agents such as vancomycin.[19,20]

One limitation with these studies was that the incidence of penicillin-resistant S pneumoniae was low, and there were few isolates with an MIC [is greater than] 2 [micro]g/mL. Therefore, based on published data, the efficacy of [Beta]-lactam agents for highly resistant pneumococcal pneumonia remains to be determined. Friedland and McCracken[20] believed that IV therapy with a [Beta]-lactam agent was adequate when the pneumococcus was of intermediate resistance, but with high levels of resistance, they noted that there had been reports of failure with some patients.[20] These patients frequently had underlying disease (ie, cancer, chronic liver disease, diabetes mellitus) and their underlying conditions may have influenced outcome. They recommended using vancomycin or imipenem for patients in whom infection with highly resistant S pneumoniae was suspected, such as nosocomial pneumonia occurring in a debilitated patient. Another consideration would be use of an extended-spectrum cephalosporin (which usually achieves levels in excess of 100 [micro]g/mL but only if the MIC of the cephalosporin for the infecting strain was [is less than or equal to] 8 [micro]g/mL.

Fortunately, the available 23 valent pneumococcal vaccine includes 85% of all penicillin-resistant S pneumoniae. Unfortunately, the incidence of vaccination remains low, with only 25 to 30% of candidates being vaccinated routinely. Additionally, the antibody response to the vaccine is not universal and only 60 to 70% of those vaccinated will develop an antibody response. This rate is reduced in the elderly, immunocompromised, or asplenic patient and is not effective in the very young ([is less than] 2 years). Because of these limitations and the minimal side effects of vaccination, some have suggested revaccination every 6 years and even sooner in certain populations. A protein conjugated pneumococcal vaccine should soon be available for the very young.[21]

A final controversy relates to the guidelines themselves.[22] These guidelines were designed to function as a review Of the recent literature and to. synthesize a large body of literature but not to replace the well-informed and dedicated practicing physician. However, concerns have arisen that these guidelines might be used as the one and only acceptable approach to the management of nosocomial pneumonia. Such an approach might be enforced by a managed care organization.

We view the development of guidelines as a positive step in the management of pneumonia. We stress, however, that it should serve only as a template for the practicing physician and in all cases the local epidemiology and resistance patterns must be taken into account. Table 1-Countries

Country HAP(*) Guidelines

Australia Yes

Austria

Canada Yes

Chile

China

Czech Republic

Finland

France Yes

Germany

Greece

Holland

Hong Kong Yes

Israel

Italy

Jamaica

Japan

Malaysia

Norway

Peru

Philippines

Saudi Arabia

Slovak Republic

South Africa

Spain

Switzerland

Sweden Yes

Taiwan

United Kingdom

United States Yes

(*) HAP = hospital-acquired pneumonia.

REFERENCES

[1] Craven DE, Steger KA, Barber TW. Preventing nosocomial pneumonia: state of the art and perspectives for the 1990’s. Am J Med 1991; 91(3B):44S-53S

[2] Craven DE, Driks MR. Pneumonia in the intubated patient. Semin Respir Infect 1987; 2:20-33

[3] Torres A, Aznar R, Gatell JM, et al. Incidence, risk, and prognosis factors of nosocomial pneumonia in mechanically ventilated patients. Am Rev Respir Dis 1990; 142:523-28

[4] Fagon JY, Chastre J, Hance A, et al. Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay. Am J Med 1993; 94:281-88

[5] American Thoracic Society. Hospital-acquired pneumonia in adults: diagnosis, assessment of severity, initial antimicrobial therapy, and preventative strategies. Am J Respir Crit Care Med 1996; 153:1711-25

[6] Huxley EJ, Viroslav J, Gray WR, et al. Pharyngeal aspiration in normal adults and patients with depressed consciousness. Am J Med 1978; 64:564-68

[7] Abraham SN, Beachey EH, Simpson WA, et al. Adherence of Streptococcus pyogenes, Escherichia coli, and Pseudomonas aeruginosa to fibronectin-coated and uncoated epithelial cells. Infect Immun 1983; 41:1261-68

[8] Woods DE, Straus DC, Johanson WG, et al. Role of fibronectin in the prevention of adherence of Pseudomonas aeruginosa to buccal cells. J Infect Dis 1981; 143:784-90

[9] Bartlett JG, O’Keefe P, Tally FP, et al. Bacteriology of hospital-acquired pneumonia. Arch Intern Med 1986; 146: 868-71

[10] Mandell LA, Marrie TJ, Niederman MS, et al. Initial antimicrobial treatment of hospital acquired pneumonia in adults: a conference report. Can J Infect Dis 1993; 4:317-21

[11] Schleupner CJ, Cobb DK. A study of the etiologies and treatment of nosocomial pneumonia in a community-based teaching hospital. Infect Control Hosp Epidemiol 1992; 13:515-25

[12] Rello J, Ricart M, Ausina V, et al. Pneumonia due to Haemophilus influenzae among mechanically ventilated patients: incidence, outcome, and risk factors. Chest 1992; 102:1562-65

[13] 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; 87:540-46

[14] Chastre J, Fagon JY. Invasive diagnostic testing should be routinely used to manage ventilated patients with suspected pneumonia. Am J Respir Crit Care Med 1994; 150:570-74

[15] Niederman MS, Torres A, Summer W. Invasive diagnostic testing is not needed routinely to manage suspected ventilator-acquired pneumonia. Am J Respir Crit Care Med 1994; 150:565-69

[16] Klugman KP. Pneumococcal resistance to antibiotics. Clin Microbiol Rev 1990; 3:171-96

[17] Pallares R, Gudiol F, Linares J, et al. Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci. N Engl J Med 1987; 317:18-22

[18] Nava JM, Bella F, Garau J, et al. Predictive factors for invasive disease due to penicillin-resistant Streptococcus pneumoniae: a population-based study. Clin Infect Dis 1994; 19:884-90

[19] Pallares R, Linares J, Vadillo M, et al. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med 1995; 333: 474-80

[20] Friedland IR, McCracken GH Jr. Management of infections caused by antibiotic-resistant Streptococcus pneumoniae. N Engl J Med 1994; 331:377-82

[21] Butler JC, Breiman RF, Campbell JF, et al. Pneumococcal polysaccharide vaccine efficacy: an evaluation of current recommendations. JAMA 1993; 270:1826-31

[22] Fein AM, Niederman MS. Guidelines for the initial management of community-acquired pneumonia: savory recipe or cookbook for disaster? Am J Respir Crit Care Med 1995; 152:1149-53

From the Division of Infectious Disease (Dr. Mandell), McMaster University, Hamilton, Ontario, Canada; and the Division of Pulmonary and Critical Care Medicine (Dr. Campbell), School of Medicine in Shreveport, Louisiana State University Medical Center.

COPYRIGHT 1998 American College of Chest Physicians

COPYRIGHT 2000 Gale Group

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