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Therapeutic guidelines for Pseudomonas aeruginosa infections
International Journal of Antimicrobial Agents 16 (2000) 103 – 106 www.ischemo.org
Therapeutic guidelines for Pseudomonas aeruginosa infections Helen Giamarellou * Athens Uni6ersity School of Medicine, Athens, Greece
Abstract Pseudomonas aeruginosa nowadays is encountered among the leading pathogen in (i) ICU pneumonia; (ii) nosocomial bacteremia and AIDS primary bacteremia; (iii) iv drug users endocarditis; (iv) exacerbations of cystis fibrosis; (v) malignant external otitis and ‘swimmers’s ear’, and (vi) contact lenses keratitis and traumatic endophthalmitis. The most vulnerable nosocomial hosts are the neutropenics and the mechanically ventilated patients in whom mortality rate exceeds 30%. Virulence of P. aeruginosa is attributed to the elaboration of various enzymes and toxins. There is also worldwide emergence of multiresistant phenotypes to antipseudomonal antibiotics. Therapeutic guidelines should therefore be based on (i) continuous resistance surveillance; (ii) in vitro synergistic interactions of antibacterial agents; (iii) pharmacodynamic properties of antibiotics interpreted by optimal dosing and appropriate frequency of administration; and (iv) current information on the necessity for combination therapy using an aminoglycoside. © 2000 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Pseudomonas aeruginosa; Pathogen; Enzymes; Toxins; Resistance
Pseudomonas aeruginosa is ubiquitous in nature, isolated from water, soil, plants, animals and man. Colonization in humans occurs mostly at the perineum, axilla and the ear because of the preference of Pseudomonas for moist environments. Respiratory equipments, antiseptic solutions, soaps, sinks, mops, vegetables, flowers, physiotherapy, hydrotherapy and swimming pools, whirlpools, and hot tubs represent the reservoirs in the hospital and also outside the hospital [1]. It is of major importance that the skin of patients with burns, the lower respiratory tract of mechanicallyventilated patients, the gastrointestinal tract of patients on anticancer chemotherapy as well as any mucosa and the skin of those treated with broad spectrum antibiotics can be colonized at rates exceeding 50% [1]. On the other hand, patient to patient transmission of P. aeruginosa via the hands of hospital personnel is a dangerous reality particularly for the immunocompromised host. P. aeruginosa is mostly a nosocomial pathogen. According to the National Nosocomial Infection Surveillance System of the CDC, the overall incidence of P. * Present address: Fourth Department of Internal Medicine, Sismanoglio General Hospital, 15126 Maroussi Attikis, Athens, Greece. Tel.: + 30-1-8039542; fax: + 30-1-8039543.
aeruginosa infection in US hospitals between 1985 and 1991 was 4.0 per 100 discharges, being the fourth most frequently isolated nosocomial pathogen. This accounted for 10.1% of all hospital-acquired infections, being also the leading cause of nosocomial pneumonia and the most common cause of ICU related respiratory tract infections [2]. In the most recent SENTRY Study [3] performed in 1997 in Canada, USA and Latin America, amongst a total of 4267 nosocomial and community acquired bloodstream infections, P. aeruginosa was the third most common isolate (10.6%) after Escherichia coli (41%) and Klebsiella spp. (17.9%). It is therefore evident that P. aeruginosa continues nowadays, although at a lower rate, to be responsible for serious infections connected with considerable morbidity and mortality. The most vulnerable subjects are the neutropenic host and the mechanically ventilated ICU patient. In the former group, mortality after 48 h of untreated bacteraemia exceeds 90% while in the latter group overall mortality reaches 69% with at least 38% of deaths directly attributed to Pseudomonas [4]. It seems that the reasons for P. aeruginosa virulence with subsequent therapeutic failures and deaths are associated with two parameters. Firstly, the microorganism elaborates a wide variety of enzymes such as proteases (elastase and alkaline protease) responsible for tissue destruction and bacterial invasion, exotoxin
0924-8579/00/$20 © 2000 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 0 ) 0 0 2 1 2 - 0
Canada Latin America
410
2153
1005 1704 Ward
199923
19985 Personal communication 199912 83 92
ICU 276
634
1996 199546
No strains tested
25
Year of publicationRef
* Not available. ** Range of resistance rates among countries.
1997 (SENTRY Study)
1995 1997
1994–95
USA
France (39 ICUs) Europe (17 western countries 1417 ICUs) Europe (5 countries 118 ICUs) Italy (15 centers) Greece (17 centers)
1991
1992 (EPIC Study)
Country
Year performed
Table 1 Resistance surveillance studies
16 28
66 12
NA 32
7–46**
46.3
63
Gentamicin
5 22
65 5
NA 27
NA
NA
36
Tobramycin
5 16
63 3
10.6 27
4–13**
NA
NA*
Amikacin
12 25
64 16
22.8 30
NA
NA
47
Ticarcillin
Resistance rates to the indicated antimicrobial (%)
4 20
64 9
12 30
5–26**
37.4
20
Piperacillin
12 14
45 13
13.4 25
2–16**
27.7
19
Ceftazidime
10 27
50 12
NA 19
NA
NA
NA
Cefepime
24 35
54 24
NA 20
NA
NA
25
Aztreonam
12 26
75 15
31.9 41
8–37**
26.3
32
Ciprofloxacin
19 15
64 11
19.3 29
19–24**
21.1
20
Imipenem
6 5
48 5
9.1 9
NA
NA
NA
Meropenem
104 H. Giamarellou / International Journal of Antimicrobial Agents 16 (2000) 103–106
H. Giamarellou / International Journal of Antimicrobial Agents 16 (2000) 103–106
A, exoenzyme S, and toxins such as leukocidin, hemolysins (phospholipase and rhamnolipid) which destruct the lung surfactants causing lung destruction leading to abscess formation and compromising antibiotic kinetics leading to the persistence of susceptible bacteria or the emergence of resistance clones [1,4]. Secondly, it is the emergence of multi-resistant P. aeruginosa strains in the hospital setting and particularly in the ICU. However, the fact that only 50% of failures were found to be associated with resistance development in ventilator-associated pneumonia [4] suggests the importance of Pseudomonas itself as a pathogen. It should also not be overlooked that P. aeruginosa produces a mucoid exopolysaccharide which offers protection from host immune factors, particularly in cystic fibrosis patients. However, inadequate initial selection of therapy was found to be connected with a significantly greater increase in selected mortality than adequate initial therapy (37 vs. 15.4% P B 0.05) [4]. When infection occurs in the ICU it usually takes up to 72 h for the microbiological confirmation of the causative pathogen including antibiotic susceptibility report. On the other hand, in the neutropenic host, about 30% of infections are microbiologically documented. Therefore, the choice of the most appropriate empirical therapy should be guided by information obtained by detailed surveillance data (see Table 1) [3,5 –8]. The physician of 2000 should always consider that P. aeruginosa will continue to be among the major pathogens in the following infective syndromes: (i) endocarditis on native valves of iv drug users and on prosthetic heart valves, (ii) pneumonia in the setting of neutropenia as well as in mechanically ventilated patients and in exacerbations of cystic fibrosis patients, (iii) primary bacteraemia mainly in neutropenia and immunocompromised patients including HIV-1 infected subject [9] with CD4 B50 cells/mm3, (iv) malignant external otitis in diabetics and ‘swimmer’s ear’, (v) meningitis and brain abscess mostly complicating neurosurgery, head trauma, intraventricular shunts and CSF leaks, (vi) keratitis associated with contact lenses and endophthalmitis complicating penetrating injuries and intraocular surgery, (vii) septic arthritis and osteomyelitis either from hematogenous spread or extention from contiguous foci related to penetrating trauma or surgery, and (viii) skin and soft tissue infections either as primary or metastatic foci, expressed as ecthyma gangrenosum, subcutaneous nodules, cellulitis, abscesses, vesicular, pustular or maculopapular lesions, bullae or even necrotizing fasciitis and gangrene. Available antibiotics with potent antipseudomonal activity both in vitro and in vivo are the aminoglycosides, ureidopenicillins, ceftazidime, cefepime, aztreonam, the carbapenems and ciprofloxacin. In
105
treating serious pseudomonal infection with b-lactams, it is particularly important to administer the optimal dose and at frequent intervals. This would ensure that plasma levels exceed the MIC for the organism for an adequate length of time and lowers the risk of emerging resistance. On the contrary, for the aminoglycosides and newer fluoroquinolones, the height of the peak levels is of great importance. Based on in vitro synergistic results after the interaction of gentamicin with carbenicillin in the late seventies as well as of ceftazidime and amikacin, combination therapy with an antipseudomonal b-lactam and an aminoglycoside became the standard therapy for serious P. aeruginosa infections and particularly for the febrile neutropenic host [10]. When newer drugs such as imipenem, meropenem and ciprofloxacin were shown to be effective as single agents in the therapy of serious P. aeruginosa infections, including a series of neutropenic patients the need for a second drug was questioned [10]. No prospective randomized comparison between monotherapy and combination drug therapy has been performed in a large number of patients who are either neutropenics or nonneutropenics, with Pseudomonas bacteraemia and sepsis. In the effort to develop a rational decision for selecting initial therapy for patients with ventilation-associated pneumonia, in a recent study infected ventilated patients were divided into four groups by crossing early or late-onset pneumonia (B or\ 7 days of mechanical ventilation) with previous antibiotic administration (B or\ 15 days). Only in the group of 84 patients with late-onset pneumonia and previous antibiotic administration, did the authors reported that carbapenems plus an aminoglycoside (or ciprofloxacin) could be justified [11]. It seemed that antimicrobial prescribing guidelines today for severe Pseudomonas infections should be individually tailored as follows: 1. The existence of various risk factors such as neutropenia and septic shock. 2. The source of infection (community or nosocomial and particularly from the ICU). 3. The length of hospitalization. 4. Previous antimicrobial therapy, and 5. Continuous local surveillance data on resistance. Prevention of Pseudomonas infections by applying strict handwashing should however not be neglected and is of extreme importance.
References [1] Pollack M, Pseudomonas aeruginosa, In: Mandell GL, Bennett JE, Dolin R, editors. Principles and Practice of Infectious Diseases. 4th ed. Churchill Livingstone, 1995. p. 1980 – 2003.
106
H. Giamarellou / International Journal of Antimicrobial Agents 16 (2000) 103–106
[2] Jarvis WR, Martine WJ. Predominant pathogens in hospital infections. J Antimicrob Chemother 1992;29 (Suppl. A):19 – 24. [3] Diekema DJ, Pfaller MA, Jones RN, et al. Survey of bloodstream infections due to gram-negative bacilli: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada and Latin America for the SENTRY Antimicrobial Surveillance Program. CID 1999;29:595 – 607. [4] 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;25:1862–7. [5] Jarlier V, Fosse T, Phillippon A, ICU Study Group. Antibiotic susceptibility in aerobic gram-negative bacilli isolated in intensive case units in 39 French teaching hospitals (ICU Study), Int. Care Med. 1996;22:1057–1065. [6] Vincent JL, Bihari DJ, Suter PM, et al. The prevalence of nosocomial infection in intensive care units in Europe: results of
.
[7]
[8]
[9]
[10]
[11]
the European prevalence of infection in Intensive Care (EPIC) Study. J Am Med Assoc 1995;74:639 – 44. Hanberger H, Garcia-Rodriguez JA, Gobernado M, et al. Antibiotic susceptibility among aerobic gram-negative bacilli in intensive care units in five European countries. French & Portuguese ICU Study Group. J Am Med Assoc 1999;281:67–71. Bonfiglio G, Carciotto V, Russo G, et al. Antibiotic resistance on Pseudomonas aeruginosa: an Italian Survey. J Antimicrob Chemother 1998;41:307 – 10. Vidal F, Mensa JM, Martinez JA. Pseudomonas aeruginosa bacteremia in patients infected with human immunodeficiency virus type 1. Eur J Clin Microbiol Infect Dis 1999;18:473–7. Klastersky J. Science and pragmatism in the treatment and prevention of neutropenic infection. J Antimicrob Chemother 1998;4 (Suppl. D):13 – 24. Trouillet JL, Chastre J, Vuagnat A, et al. Ventilator-associated pneumonia caused by potentially drug-resistant bacteria. Am J Resp Crit Care Med 1998;157:531 – 9.
Therapeutic guidelines for Pseudomonas aeruginosa infections Helen Giamarellou * Athens Uni6ersity School of Medicine, Athens, Greece
Abstract Pseudomonas aeruginosa nowadays is encountered among the leading pathogen in (i) ICU pneumonia; (ii) nosocomial bacteremia and AIDS primary bacteremia; (iii) iv drug users endocarditis; (iv) exacerbations of cystis fibrosis; (v) malignant external otitis and ‘swimmers’s ear’, and (vi) contact lenses keratitis and traumatic endophthalmitis. The most vulnerable nosocomial hosts are the neutropenics and the mechanically ventilated patients in whom mortality rate exceeds 30%. Virulence of P. aeruginosa is attributed to the elaboration of various enzymes and toxins. There is also worldwide emergence of multiresistant phenotypes to antipseudomonal antibiotics. Therapeutic guidelines should therefore be based on (i) continuous resistance surveillance; (ii) in vitro synergistic interactions of antibacterial agents; (iii) pharmacodynamic properties of antibiotics interpreted by optimal dosing and appropriate frequency of administration; and (iv) current information on the necessity for combination therapy using an aminoglycoside. © 2000 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Pseudomonas aeruginosa; Pathogen; Enzymes; Toxins; Resistance
Pseudomonas aeruginosa is ubiquitous in nature, isolated from water, soil, plants, animals and man. Colonization in humans occurs mostly at the perineum, axilla and the ear because of the preference of Pseudomonas for moist environments. Respiratory equipments, antiseptic solutions, soaps, sinks, mops, vegetables, flowers, physiotherapy, hydrotherapy and swimming pools, whirlpools, and hot tubs represent the reservoirs in the hospital and also outside the hospital [1]. It is of major importance that the skin of patients with burns, the lower respiratory tract of mechanicallyventilated patients, the gastrointestinal tract of patients on anticancer chemotherapy as well as any mucosa and the skin of those treated with broad spectrum antibiotics can be colonized at rates exceeding 50% [1]. On the other hand, patient to patient transmission of P. aeruginosa via the hands of hospital personnel is a dangerous reality particularly for the immunocompromised host. P. aeruginosa is mostly a nosocomial pathogen. According to the National Nosocomial Infection Surveillance System of the CDC, the overall incidence of P. * Present address: Fourth Department of Internal Medicine, Sismanoglio General Hospital, 15126 Maroussi Attikis, Athens, Greece. Tel.: + 30-1-8039542; fax: + 30-1-8039543.
aeruginosa infection in US hospitals between 1985 and 1991 was 4.0 per 100 discharges, being the fourth most frequently isolated nosocomial pathogen. This accounted for 10.1% of all hospital-acquired infections, being also the leading cause of nosocomial pneumonia and the most common cause of ICU related respiratory tract infections [2]. In the most recent SENTRY Study [3] performed in 1997 in Canada, USA and Latin America, amongst a total of 4267 nosocomial and community acquired bloodstream infections, P. aeruginosa was the third most common isolate (10.6%) after Escherichia coli (41%) and Klebsiella spp. (17.9%). It is therefore evident that P. aeruginosa continues nowadays, although at a lower rate, to be responsible for serious infections connected with considerable morbidity and mortality. The most vulnerable subjects are the neutropenic host and the mechanically ventilated ICU patient. In the former group, mortality after 48 h of untreated bacteraemia exceeds 90% while in the latter group overall mortality reaches 69% with at least 38% of deaths directly attributed to Pseudomonas [4]. It seems that the reasons for P. aeruginosa virulence with subsequent therapeutic failures and deaths are associated with two parameters. Firstly, the microorganism elaborates a wide variety of enzymes such as proteases (elastase and alkaline protease) responsible for tissue destruction and bacterial invasion, exotoxin
0924-8579/00/$20 © 2000 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 0 ) 0 0 2 1 2 - 0
Canada Latin America
410
2153
1005 1704 Ward
199923
19985 Personal communication 199912 83 92
ICU 276
634
1996 199546
No strains tested
25
Year of publicationRef
* Not available. ** Range of resistance rates among countries.
1997 (SENTRY Study)
1995 1997
1994–95
USA
France (39 ICUs) Europe (17 western countries 1417 ICUs) Europe (5 countries 118 ICUs) Italy (15 centers) Greece (17 centers)
1991
1992 (EPIC Study)
Country
Year performed
Table 1 Resistance surveillance studies
16 28
66 12
NA 32
7–46**
46.3
63
Gentamicin
5 22
65 5
NA 27
NA
NA
36
Tobramycin
5 16
63 3
10.6 27
4–13**
NA
NA*
Amikacin
12 25
64 16
22.8 30
NA
NA
47
Ticarcillin
Resistance rates to the indicated antimicrobial (%)
4 20
64 9
12 30
5–26**
37.4
20
Piperacillin
12 14
45 13
13.4 25
2–16**
27.7
19
Ceftazidime
10 27
50 12
NA 19
NA
NA
NA
Cefepime
24 35
54 24
NA 20
NA
NA
25
Aztreonam
12 26
75 15
31.9 41
8–37**
26.3
32
Ciprofloxacin
19 15
64 11
19.3 29
19–24**
21.1
20
Imipenem
6 5
48 5
9.1 9
NA
NA
NA
Meropenem
104 H. Giamarellou / International Journal of Antimicrobial Agents 16 (2000) 103–106
H. Giamarellou / International Journal of Antimicrobial Agents 16 (2000) 103–106
A, exoenzyme S, and toxins such as leukocidin, hemolysins (phospholipase and rhamnolipid) which destruct the lung surfactants causing lung destruction leading to abscess formation and compromising antibiotic kinetics leading to the persistence of susceptible bacteria or the emergence of resistance clones [1,4]. Secondly, it is the emergence of multi-resistant P. aeruginosa strains in the hospital setting and particularly in the ICU. However, the fact that only 50% of failures were found to be associated with resistance development in ventilator-associated pneumonia [4] suggests the importance of Pseudomonas itself as a pathogen. It should also not be overlooked that P. aeruginosa produces a mucoid exopolysaccharide which offers protection from host immune factors, particularly in cystic fibrosis patients. However, inadequate initial selection of therapy was found to be connected with a significantly greater increase in selected mortality than adequate initial therapy (37 vs. 15.4% P B 0.05) [4]. When infection occurs in the ICU it usually takes up to 72 h for the microbiological confirmation of the causative pathogen including antibiotic susceptibility report. On the other hand, in the neutropenic host, about 30% of infections are microbiologically documented. Therefore, the choice of the most appropriate empirical therapy should be guided by information obtained by detailed surveillance data (see Table 1) [3,5 –8]. The physician of 2000 should always consider that P. aeruginosa will continue to be among the major pathogens in the following infective syndromes: (i) endocarditis on native valves of iv drug users and on prosthetic heart valves, (ii) pneumonia in the setting of neutropenia as well as in mechanically ventilated patients and in exacerbations of cystic fibrosis patients, (iii) primary bacteraemia mainly in neutropenia and immunocompromised patients including HIV-1 infected subject [9] with CD4 B50 cells/mm3, (iv) malignant external otitis in diabetics and ‘swimmer’s ear’, (v) meningitis and brain abscess mostly complicating neurosurgery, head trauma, intraventricular shunts and CSF leaks, (vi) keratitis associated with contact lenses and endophthalmitis complicating penetrating injuries and intraocular surgery, (vii) septic arthritis and osteomyelitis either from hematogenous spread or extention from contiguous foci related to penetrating trauma or surgery, and (viii) skin and soft tissue infections either as primary or metastatic foci, expressed as ecthyma gangrenosum, subcutaneous nodules, cellulitis, abscesses, vesicular, pustular or maculopapular lesions, bullae or even necrotizing fasciitis and gangrene. Available antibiotics with potent antipseudomonal activity both in vitro and in vivo are the aminoglycosides, ureidopenicillins, ceftazidime, cefepime, aztreonam, the carbapenems and ciprofloxacin. In
105
treating serious pseudomonal infection with b-lactams, it is particularly important to administer the optimal dose and at frequent intervals. This would ensure that plasma levels exceed the MIC for the organism for an adequate length of time and lowers the risk of emerging resistance. On the contrary, for the aminoglycosides and newer fluoroquinolones, the height of the peak levels is of great importance. Based on in vitro synergistic results after the interaction of gentamicin with carbenicillin in the late seventies as well as of ceftazidime and amikacin, combination therapy with an antipseudomonal b-lactam and an aminoglycoside became the standard therapy for serious P. aeruginosa infections and particularly for the febrile neutropenic host [10]. When newer drugs such as imipenem, meropenem and ciprofloxacin were shown to be effective as single agents in the therapy of serious P. aeruginosa infections, including a series of neutropenic patients the need for a second drug was questioned [10]. No prospective randomized comparison between monotherapy and combination drug therapy has been performed in a large number of patients who are either neutropenics or nonneutropenics, with Pseudomonas bacteraemia and sepsis. In the effort to develop a rational decision for selecting initial therapy for patients with ventilation-associated pneumonia, in a recent study infected ventilated patients were divided into four groups by crossing early or late-onset pneumonia (B or\ 7 days of mechanical ventilation) with previous antibiotic administration (B or\ 15 days). Only in the group of 84 patients with late-onset pneumonia and previous antibiotic administration, did the authors reported that carbapenems plus an aminoglycoside (or ciprofloxacin) could be justified [11]. It seemed that antimicrobial prescribing guidelines today for severe Pseudomonas infections should be individually tailored as follows: 1. The existence of various risk factors such as neutropenia and septic shock. 2. The source of infection (community or nosocomial and particularly from the ICU). 3. The length of hospitalization. 4. Previous antimicrobial therapy, and 5. Continuous local surveillance data on resistance. Prevention of Pseudomonas infections by applying strict handwashing should however not be neglected and is of extreme importance.
References [1] Pollack M, Pseudomonas aeruginosa, In: Mandell GL, Bennett JE, Dolin R, editors. Principles and Practice of Infectious Diseases. 4th ed. Churchill Livingstone, 1995. p. 1980 – 2003.
106
H. Giamarellou / International Journal of Antimicrobial Agents 16 (2000) 103–106
[2] Jarvis WR, Martine WJ. Predominant pathogens in hospital infections. J Antimicrob Chemother 1992;29 (Suppl. A):19 – 24. [3] Diekema DJ, Pfaller MA, Jones RN, et al. Survey of bloodstream infections due to gram-negative bacilli: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada and Latin America for the SENTRY Antimicrobial Surveillance Program. CID 1999;29:595 – 607. [4] 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;25:1862–7. [5] Jarlier V, Fosse T, Phillippon A, ICU Study Group. Antibiotic susceptibility in aerobic gram-negative bacilli isolated in intensive case units in 39 French teaching hospitals (ICU Study), Int. Care Med. 1996;22:1057–1065. [6] Vincent JL, Bihari DJ, Suter PM, et al. The prevalence of nosocomial infection in intensive care units in Europe: results of
.
[7]
[8]
[9]
[10]
[11]
the European prevalence of infection in Intensive Care (EPIC) Study. J Am Med Assoc 1995;74:639 – 44. Hanberger H, Garcia-Rodriguez JA, Gobernado M, et al. Antibiotic susceptibility among aerobic gram-negative bacilli in intensive care units in five European countries. French & Portuguese ICU Study Group. J Am Med Assoc 1999;281:67–71. Bonfiglio G, Carciotto V, Russo G, et al. Antibiotic resistance on Pseudomonas aeruginosa: an Italian Survey. J Antimicrob Chemother 1998;41:307 – 10. Vidal F, Mensa JM, Martinez JA. Pseudomonas aeruginosa bacteremia in patients infected with human immunodeficiency virus type 1. Eur J Clin Microbiol Infect Dis 1999;18:473–7. Klastersky J. Science and pragmatism in the treatment and prevention of neutropenic infection. J Antimicrob Chemother 1998;4 (Suppl. D):13 – 24. Trouillet JL, Chastre J, Vuagnat A, et al. Ventilator-associated pneumonia caused by potentially drug-resistant bacteria. Am J Resp Crit Care Med 1998;157:531 – 9.