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Antibiotic resistance among gram-negative nosocomial pathogens in the intensive care unit: results of 6-year body-site monitoring
CLINICAL THERAPEUTICS®/VOL.19, NO. 4, 1997
Antibiotic Resistance Among Gram-Negative Nosocomial Pathogens in the Intensive Care Unit: Results of 6-Year Body-Site Monitoring Bruno Bar~ib, MD, PhD, Ivan Beus, MD, PhD, Eduard Marton, MD, Josip Himbele, MD, Nata~a Kuzmanovib, MD, Danijela Bejuk, MD, Arijana Boras, MD, and Igor Klinar, MD UniversityHospitalfor Infectious Diseases "dr Fran Mihaljevic," Zagreb, Croatia
ABSTRACT Results of 6-year body-site monitoring in an intensive care unit (ICU) are presented and antimicrobial resistance of gramnegative isolates analyzed. The study included 622 patients. Six hundred thirtyfive bacterial isolates--causes of nosocomial sepsis, pneumonia, and urinary tract infections (UTIs)--were tested during the study. Gram-negative bacteria were the predominant isolates, causing 65% of cases of sepsis, 78.7% of pneumonias, and 70.2% of UTIs. Gram-negative isolates (454) were highly resistant to antimicrobials commonly used in the ICU, with the exception of imipenem. Resistance was 1.1% among pathogens responsible for UTIs, 6.7% among those causing sepsis, and 13.6% among those responsible for pneumonia. Klebsiella pneumoniae associated with pneumonia and sepsis was significantly less resistant to cipro0149-2918/97/$3-50
floxacin than were isolates from urine (22.8% and 13.9%, respectively, vs 44.4%). Pseudomonasaeruginosa swains responsible for pneumonia were less resistant to ceftazidime than were isolates causing sepsis and UTI (35.7% vs 51.3% and 51.5%, respectively). Acinetobacter calcoaceticus strains associated with UTI were significantly more resistant to netilmicin than were strains responsible for sepsis and pneumonia (83.3% vs 40.3% and 42.6%, respectively). The study confirmed that in addition to focused microbiologic surveillance, multiple-body-site monitoring can provide unique information about the sensitivity of the pathogens involved. The results suggest that antimicrobial resistance among nosocomial pathogens depends on the site of infection or the type of microbiologic specimen. Key words:antibiotic resistance, nosocomial infection, gram-negative bacteria, intensive care unit. 691
CLINICAL THERAPEUTICS*
INTRODUCTION Nosocomial infections are a common problem in modem medicine, particularly among patients treated in the intensive care unit (ICU). 1-3 Often caused by bacteria that are resistant to multiple antibiotics,4 these infections delay optimal antimicrobial treatment and adversely affect outcomes .5 While of crucial importance, the choice of empiric antibiotic therapy is often limited in countries with high rates of antibiotic resistance, 6-s necessitating the use of newer, more expensive antimicrobial agents. Because problems of resistance within hospitals are often specific to the ICU, empiric therapy should be based on the results of focused microbiologic surveillance. 9-H Such surveillance, however, relies on pooled data reflecting the antibiotic susceptibilities of multiple isolates obtained from various anatomic sites; thus the results may be misleading. 12 For optimal guidance in selecting empiric therapy, antibiotic susceptibilities of body-site-specific pathogens should be determined. 13 This study involved body-site monitoring of the pathogens responsible for nosocomial sepsis, pneumonia, and urinary tract infections (UTIs) in critically ill patients treated in the ICU. We began with the hypothesis that gram-negative pathogens isolated from different body sites differ in their antibiotic susceptibility patterns. PATIENTS AND METHODS This prospective, 6-year study (January 1, 1990, to December 31, 1995) involved 622 patients treated in our ICU for more than 48 hours because of a life-threatening nosocomial infection. The infections were
692
defined according to criteria established by the Centers for Disease Control and Prevention. 14
Bacteriologic Assessment The frequency with which particular organisms were isolated in nosocomial infections of the bloodstream, respiratory tract, and urinary tract, as well as their antibiotic resistance, was assessed by examining cultures of specimens from the relevant body site. Specimens included tracheal aspirates or bronchial microlavage samples, blood from a peripheral vein and/or indwelling central venous catheter, and urine, respectively. 15 We used only the initial isolates of identified organisms. To avoid statistical bias, if the same pathogen was isolated from the bloodstream and from the urine or tracheal aspirates, it was regarded as the cause of the UTI or pneumonia but not of the sepsis. 13 Blood samples were obtained at the onset of a new febrile episode. When blood cultures grew common contaminants-Corynebacterium, Bacillus species, coagulase-negative staphylococci, or Propionibacterium acnes--at least two blood cultures had to be positive for the same organism within a 24-hour period for the case to be regarded as true bacteremia. 16 Tracheal aspiration and bronchial microlavage were performed through a sterile catheter when respiratory infection was suspected. All urine cultures testing positive for significant UTI (>105 bacteria/mL of urine) were included. Urine was taken once weekly. Specimens were cultured and bacteria identified using standard microbiologic techniques. Antibiotic susceptibility was determined by disk diffusion.
B. BARSI~ ET AL.
Statistical Analysis
The chi-square test was used to evaluate the statistical significance of observed differences in antibiotic susceptibility of the gram-negative pathogens isolated in the three types of nosocomial infection studied. Continuous variables were tested by using the Scheff6 test. ~S~TS Six hundred thirty-five bacterial isolates from patients with nosocomial infections were tested in the course of the study. Table I lists the species and distribution of the infecting organisms. Gram-negative bacteria were the predominant isolates, causing 65% of cases of sepsis, 78.7% of pneumonias, and 70.2% of UTIs. Acinetobacter calcoaceticus (baumannii), Pseudomonas aeruginosa, and Klebsiella
pneumoniae were the most frequently identified pathogens, except among UTIs, where Enterococcus species were found more often than A caicoaceticus. The respiratory tract was the most fertile source of bacteria. The gram-negative pathogens were highly resistant to all the antimicrobial agents commonly used in our ICU except for imipenem (Table II). The isolates associated with primary bloodstream infections (sepsis) were significantly less resistant to netilmicin and ciprofloxacin than were those responsible for respiratory tract infections and UTIs. The isolates causing UTIs were more sensitive to cefotaxime and ceftriaxone than were those associated with sepsis and pneumonia. The pathogens that caused pneumonia were less resistant to ceftazidime and more resistant to imipenem than were those that caused the other two types of
Table I. Microorganisms associated with nosocomial infections. No. (%) of Isolates
Microorganism Escherichia coli Klebsiella pneumoniae Citrobacterfreundii Serratia marcescens Proteus mirabilis Enterobacter sp Pseudomonas aeruginosa Acinetobacter calcoaceticus Other gram-negative organisms Enterococcus sp Staphylococcus aureus Other staphylococci Candida sp Other gram-positive organisms
Sepsis (251)
Pneumonia (253)
Urinary Tract Infections (131)
2 (0.8) 36 (14.3) 1 (0.4) 5 (2.0) 1 (0.4) 12 (4.8) 39 (15.5) 62 (24.7) 5 (2.0) 29 (11.6) 13 (5.2) 25 (10.0) 18 (7.2) 3 (1.2)
5 (2.0) 35 (13.8) 2 (0.8) 1 (0.4) 6 (2.4) 7 (2.8) 84 (33.2) 54 (21.3) 5 (2.0) 5 (2.0) 30 (11.9) 9 (3.6) 5 (2.0) 5 (2.0)
4 (3.1) 27 (20.6) 2 (1.5) 4 (3.1) 9 (6.9) 33 (25.2) 12 (9.2) 1 (0.8) 17 (13.0) 1 (0.8) 21 (16.0) -
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Table II. Resistance rates among gram-negative isolates causing nosocomial infections. No. (%) of Resistant Isolates
Antibiotic Gentamicin Netilmicin Amikacin Cefotaxime Ceftriaxone Ceftazidime Ciprofioxacin Pefloxacin Imipenem
Sepsis (163)
Pneumonia (199)
Urinary Tract Infections (92)
P
134 (82.2) 72 (44:2) 95 (58.3) 144 (88.3) 136 (83.4) 120 (73.6) 70 (42.9) 125 (76.7) 11 (6.7)
156 (78.4) 107 (53.8) 116 (58.3) 165 (82.9) 161 (80.9) 116 (58.3) 117 (58.8) 165 (82.9) 27 (13.6)
80 (87.0) 61 (66.3) 49 (53:2) 68 (73.9) 61 (66.3) 59 (64.1) 58 (63.0) 76 (82.6) 1 (1.1)
NS 0.0029 NS 0.0129 0.0036 0.0042 0.0005 NS 0.0531
infection, although imipenem resistance did not approach statistical significance. When resistance rates of Kpneumoniae, P aeruginosa, and A calcoaceticus were evaluated (Tables III to V), K pneumoniae associated with pneumonia and sepsis was less resistant to ciprofloxacin than were isolates from urine. A calcoaceticus associated with pneumonia and sepsis was less resistant to netilmicin than were strains causing UTI. P aeruginosa strains responsible for pneumonia were less resistant to ceftazidime than were isolates causing sepsis and UTI, although the difference was not statsfically significant (P = 0.1413). Resistance among the three major gram-negative pathogens was also tested without regard to their clinical relevance (Tables VI to VIII). Respiratory tract isolates of K pneumoniae were significantly less resistant to all three aminoglycosides than were those from blood or urine (P = 0.0293 for gentamicin, P =.0.0002 for netilmicin, and P = 0.0472 for amikacin). Urinary isolates were more resistant to 694
ciprofloxacin. Probably because of the small numbers of blood isolates of K pneumoniae, statistical significance was not achieved (P = 0.909). P aeruginosa strains from the respiratory tract were more sensitive to gentamicin, netilmicin, and ciprofioxacin than were those from blood or urine. A calcoaceticus strains from the blood and respiratory tract showed less resistance to netilmicin than did those from urine. Most strains of this pathogen (98%) were further classified as
A baumannii. The average ICU stay until the onset of nosocomial infection and isolation of pathogens was 25 days for sepsis, 15 days for pneumonia, and 31 days for UTI (P < 0.001). DISCUSSION AND C O N C L U S I O N S Monitoring microbial frequency and susceptibility patterns is a major component of infection control programs in medical facilities and is the first step toward se-
B. BARSI(2 ET AL.
Table III. Resistance rates among infection-causing Klebsiella pneumoniae isolates. No. (%) of Resistant Isolates
Antibiotic Gentamicin Netilmicin Amikacin Cefotaxime Ceftriaxone Ceftazidime Ciprofloxacin Pefloxacin Imipenem
Sepsis (36)
Pneumonia (35)
Urinary Tract Infections (27)
P
30 (83.3) 14 (38.9) 23 (63.9) 28 (77.8) 26 (72.2) 28 (77.8) 5 (13.9~ 27 (75.0) 1 (2.8)
25 (71.4) 12 (34.3) 19 (54.3) 22 (62.8) 22 (62.8) 19 (54.3) 8 (22.8) 21 (60.0) 1 (2.9)
25 (92.6) 14 (51.8) 18 (66.7) 20 (74.1) 17 (63.0) 20 (74.1) 12 (44.4) 22 (81.5) 1 (3.7)
NS NS NS NS NS NS 0.0204 NS *
*Not done because of low number in cell. Table IV. Resistance rates among infection-causing Pseudomonas aeruginosa isolates. No. (%) of Resistant Isolates
Antibiotic Gentamicin Netilmicin Amikacin Cefotaxime Ceftriaxone Ceftazidime Ciprofloxacin Pefloxacin Imipenem
Sepsis (39)
Pneumonia (84)
Urinary Tract Infections (33)
P
31 (79.5) 25 (64.1) 16 (41.0) 35 (89.7) 34 (87.2) 20 (51.3) 23 (59.0) 34 (87.2) 9 (23.1)
77 (91.7) 55 (65.5) 42 (50.0) 73 (86.9) 70 (83.3) 30 (35.7) 55 (65.5) 73 (86.9) 17 (20.2)
27 (81.8) 26 (78.8) 18 (54.5) 26 (78.8) 26 (78.8) 17 (51.5) 26 (78.8) 28 (84.8) -
NS NS NS NS NS NS NS NS NS
lecting the best antibiotic for empiric therapy. In addition to unit-specific surveillance, monitoring by infection site may help facilitate choosing the most appropriate antimicrobial agent. 12,17 Since 1988, our ICU has carded out focal surveillance using specimens obtained
from peripheral veins or central venous catheters, tracheal aspirate or bronchial microlavage samples, urine, and gastric secretions (data not presented). Preliminary results of body-site monitoring had suggested differences in the antibiotic resistance of gram-negative pathogens ac695
CLINICAL THERAPEUTICS®
Table V. Resistance rates among infection-causing Acinetobacter calcoaceticus isolates. No. (%) of Resistant Isolates
Antibiotic Gentamicin Netilmicin Amikacin Cefotaxime Ceftriaxone Ceftazidime Ciprofloxacin Pefloxacin Imipenem
Sepsis (62)
Pneumonia (54)
Urinary Tract Infections (12)
57 (91.9) 25 (40.3) 45 (72.6) 60 (96.8) 58 (93.5) 58 (93.5) 39 (62.9) 51 (82.3) -
50 (92.6) 23 (42.6) 40 (74.1) 52 (96.3) 52 (96.3) 51 (94.4) 41 (75.9) 52 (96.3) 1 (1.9)
12 (100) 10 (83.3) 6 (50.0) 12 (100) 11 (91.7) 10 (83.3) 10 (83.3) 12 (100) -
P NS 0.0255 NS NS NS NS NS 0.0361 -
Table VI. Resistance rates among infection-causing Klebsiella pneumoniae isolates regardless o f clinical relevance. No. (%) of Resistant Isolates
Antibiotic Gentamicin Netilmicin Amikacin Cefotaxime Ceftriaxone Ceftazidime Ciprofloxacin Pefloxacin Imipenem
Respiratory Secretions (89)
Blood (31 )
Urine (54)
P
64 (71.9) 23 (25.8) 41 (46.1) 53 (59.6) 54 (60.7) 55 (61.8) 15 (16.9) 53 (59.6) 1 (1.1)
28 (90.3) 13 (41.9) 20 (64.5) 24 (77.4) 22 (71.0) 24 (77.4) 3 (9.7) 24 (77.4) 1 (32)
48 (88.9) 30 (55.6) 35 (64.8) 35 (64.8) 33 (61.1) 38 (70.4) 15 (27.8) 38 (70.4) 1 (1.9)
0.0293 0.0002 0.0472 NS NS NS NS NS -
cording to the material analyzed. 7 To conf i n n these findings, we undertook this prospective, 6-year study in critically ill patients with nosocomial infections and found that gram-negative pathogens had different antibiotic resistance rates according to the type of nosocomial infection that was present. 696
Resistance to the most frequently used antimicrobial agents was extremely high in our ICU. The exception was imipenem, to which resistance was low in all types o f infection. If empiric therapy was selected solely on the basis of at least 85% inhibition of a given bacterial species, in our ICU only imipenem would be accept-
B. BARSIC ET AL.
Table VII. Resistance rates among Pseudomonas aeruginosa isolates regardless of clinical relevance. No. (%) of Resistant Isolates
Antibiotic Gentamicin Netilmicin Amikacin Cefotaxime Ceftriaxone Ceftazidime Ciprofloxacin Pefloxacin Imipenem
Respiratory Secretions (177)
Blood (22)
Urine (48)
P
102 (57.6) 89 (50.3) 65 (36.7) 140 (79.1) 127 (71.8) 55 (31.1) 98 (55.4) 138 (78.0) 25 (14.1)
16 (72.7) 15 (68.2) 10 (45.5) 19 (86.4) 18 (81.8) 9 (40.9) 13 (59.1) 20 (90.9) 3 (13.6)
40 (83.3) 37 (77.1) 26 (54.2) 42 (87_5) 38 (79.2) 21 (43.8) 39 (81.3) 43 (89.6) 3 (6.3)
0.0030* 0.0021 0.0837 NS NS NS 0.0049 NS NS
*Respiratorysecretionswere comparedwith urine becausefewerthan five sensitive strains were isolatedfromblood. Table VIII. Resistance rates among Acinetobacter calcoaceticus isolates regardless of clinical relevance. No. (%) of Resistant Isolates
Antibiotic Gentamicin Netilmicin Amikacin Cefotaxime Ceftriaxone Ceftazidime Ciprofloxacin Pefloxacin Imipenem
Respiratory Secretions (142)
Blood (50)
Urine (35)
P
129 (90.8) 41 (28.9) 111 (78.2) 133 (93.7) 133 (93.7) 131 (92.3) 105 (73.9) 129 (90.8) 2 (1.4)
45 (90.0) 19 (38.0) 38 (76.0) 48 (96.0) 48 (96.0) 48 (96.0) 33 (66.0) 42 (84.0) 1 (2.0)
34 (97.1) 22 (62.9) 25 (71.4) 33 (94.3) 32 (91.4) 32 (91.4) 28 (80.0) 32 (91.4) -
NS 0.0008 0.6948 NS NS NS NS NS -
able for all types o f nosocomial infections. Investigators in countries with much lower rates o f resistance in the ICU have made similar observations, is Analysis of susceptibility data over several years can readily identify changes in resistance patterns. Such changes were not demon-
strated in our study, except for the emergence of imipenem-resistant P aeruginosa strains. Despite that, the number of imipenem-resistant isolates did not significantly increase, probably because of the somewhat restricted use of this drug. Similar findings have been noted elsewhere. 193°
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Our study uncovered significant differences associated with the type of infection. Pathogens responsible for sepsis were less resistant to aminoglycosides, and those causing UTIs were less resistant to third-generation cephalosporins. Isolates in pneumonia were less resistant to ceftazidime, probably because P aeruginosa was frequently identified. However, few studies support our hypothesis. Gaynes and Culver 21 found higher imipenem resistance among gramnegative bacteria from the respiratory tract. In a Swedish study, 22 isolates from the blood generally were more sensitive to all cephalosporins than were isolates collected from urine and wounds during the same period. In our study, Pseudomonas species from the respiratory tract were less resistant to ceftazidime than were isolates from the blood, whereas Koonitz 12 found quite the opposite. When we selectively analyzed particular pathogens, differences in sensitivity to some antimicrobial agents were confirmed. Probably these differences were not more dramatic because of the low number of strains tested. The reason for the observed differences is not clear. The time of hospitalization could not have influenced the resuits, because there was no uniform pattern of differences in antibiotic sensitivity. It is possible that the rate of selection of resistant pathogens differs among materials because of differences in local antibiotic concentrations, but this remains to be proved. Our study confirmed that in addition to focused microbiologic surveillance, monitoring of multiple body sites can provide valuable information about the antibiotic sensitivity of the pathogens involved. Our results suggest that antimicrobial resis698
tance among nosocomial pathogens depends on the site of infection (or type of microbiologic specimen), as well as on noncritical antibiotic use, type of ICU, and type and size of hospital. Multicenter studies in countries with low or medium rates of antibiotic resistance may further clarify this issue, and even greater differences in antibiotic sensitivity based on the site of infection may be seen. Composite antibiograms should be developed from the individual minimum inhibitory concentrations of bodysite--specific nosocomial pathogens. 4,13
ACKNOWLEDGMENTS Publication of this paper is sponsored by Merck & Co., Inc. The research was partially supported by a grant from the Croatian Ministry of Science.
Address correspondence to: Bruno Bar, re, University Hospital for Infectious Diseases "dr Fran Mihaljevic," Zagreb, Croatia. REFERENCES
1. Ferraris VA, Propp ME. Outcome in critical care patients: A multivariate study. Crit Care Med. 1992;20:967-976. 2. Kappstein I, Daschner FD. Nosocomial infections in intensive care units. Curr Opin Infect Dis. 1990;3:509-516. 3. Trilla A. Epidemiology of nosocomial infections in adult intensive care units. Intensive Care Med. 1994;20(Suppl 3):S1-$4.
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4. Chen HY, Yuan M, Ibrahim-Elmagboul IB, Livermore DM. National survey of susceptibility to antimicrobials amongst clinical isolates of Pseudomonas aeruginosa. J Antimicrob Chemother. 1995;35: 521-534. 5. Shlaes DM. The clinical relevance of Enterobacter infections. Clin Ther. 1993;15 (Suppl A [US]):21-28. 6. Verbist L. Epidemiology and sensitivity of 8625 ICU and hematology/oncology bacterial isolates in Europe. Scand J Infect Dis. 1993;91(Suppl):14--24. 7. Bar~i'cB, Beus I, Marton E, et al. Bolni'cke infekcije i rezistencija na neke novije antibiotike u jedinici intenzivne skrbi: Ovisnost o dijagnosticko-terapijskim zahvatima. Lijec Vjesn. 1991;113: 401--404. 8. Kaleni'c S, Sekuli~ A, Franceffc I, et al. Empirical therapy of sepsis based on local resistance at a neurosurgical intensive care unit. Neurol Croat. 1993;42:47-56. 9. Weinstein RA, Kabins SA. Strategies for prevention and control of multiple drugresistant nosocomial infection. Am J Med. 1981 ;70:449-454. 10. Weinstein MP, Murphy JR, Reller LB, Lichtenstein KA. The clinical significance of positive blood cultures: A comprehensive analysis of 500 episodes of bacteremia and fungemia in adults, II: Clinical observations, with special reference to factors influencing prognosis. Rev Infect Dis. 1983;5:54--70. 11. Stratton CW, Ratner H, Johnston PE, Schaffner W. Focused microbiologic surveillance by specific hospital unit as a sensitive means of defining antimicrobial resistance problems. Diagn Microbiol Infect Dis. 1992;15:11S-18S.
12. Koonitz FP. Microbial resistance surveillance techniques: Blood culture versus multiple body site monitoring. Diagn Microbial Infect Dis. 1992;15:31S-35S. 13. Martin MA, Pfaller MA, Rojas PB, et al. In-vitro susceptibility of nosocomial gram-negative bloodstream pathogens to quinolones and other antibiotics: A statistical approach. J Antimicrob Chemother. 1989;23:353-361. 14. Garner JS, Jarvis WR, Emori TG, et al. CDC definitions for nosocomial infections, 1988. Am J Infect Control. 1988; 16: 128-140. 15. Acourt CHD, Garrard CS, Crook D, et al. Microbiological lung surveillance in mechanically ventilated patients, using nondirected bronchial lavage and quantitative culture. QJM. 1993;86:635-648. 16. MacGregor RR, Beaty HN. Evaluation of positive blood cultures. Guidelines for early differentiation of contaminants from valid positive cultures. Arch Intern Med. 1972;130:84-87. 17. Norris SM, Guenthner SH, Wenzel RE Comparative activity of seven extendedspectrum cephalosporins against gramnegative bacilli from blood cultures. J Antimicrob Chemother. 1985;16:183-188. 18. Pierson CL, Friedman BA. Comparison of susceptibility to beta-lactam antimicrobial agents among bacteria isolated from intensive care units. Diagn Microbiol Infect Dis. 1992; 15:19S-30S. 19. Bryce EA, Smith JA. Focused microbiological surveillance and gram-negative beta-lactamase mediated resistance in an intensive care unit. Infect Control Hosp Epidemiol. 1995;16:331-334.
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20. Fass RJ, Bamishan J, Ayers LW. Emergence of bacterial resistance to imipenem and ciprofloxacin in a university hospital. J Antimicrob Chemother. 1995;36:343-353. 21. Gaynes RP, Culver DH. Resistance to imipenem among selected gram-negative bacilli in the United States. Infect Control Hosp Epidemiol. 1992;13:10-14.
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22. Walder M, Karlsson E, Nilsson B. Sensitivity of 880 blood culture isolates to 22 antibiotics. Scand J Infect Dis. 1994;26: 67-75.
Antibiotic Resistance Among Gram-Negative Nosocomial Pathogens in the Intensive Care Unit: Results of 6-Year Body-Site Monitoring Bruno Bar~ib, MD, PhD, Ivan Beus, MD, PhD, Eduard Marton, MD, Josip Himbele, MD, Nata~a Kuzmanovib, MD, Danijela Bejuk, MD, Arijana Boras, MD, and Igor Klinar, MD UniversityHospitalfor Infectious Diseases "dr Fran Mihaljevic," Zagreb, Croatia
ABSTRACT Results of 6-year body-site monitoring in an intensive care unit (ICU) are presented and antimicrobial resistance of gramnegative isolates analyzed. The study included 622 patients. Six hundred thirtyfive bacterial isolates--causes of nosocomial sepsis, pneumonia, and urinary tract infections (UTIs)--were tested during the study. Gram-negative bacteria were the predominant isolates, causing 65% of cases of sepsis, 78.7% of pneumonias, and 70.2% of UTIs. Gram-negative isolates (454) were highly resistant to antimicrobials commonly used in the ICU, with the exception of imipenem. Resistance was 1.1% among pathogens responsible for UTIs, 6.7% among those causing sepsis, and 13.6% among those responsible for pneumonia. Klebsiella pneumoniae associated with pneumonia and sepsis was significantly less resistant to cipro0149-2918/97/$3-50
floxacin than were isolates from urine (22.8% and 13.9%, respectively, vs 44.4%). Pseudomonasaeruginosa swains responsible for pneumonia were less resistant to ceftazidime than were isolates causing sepsis and UTI (35.7% vs 51.3% and 51.5%, respectively). Acinetobacter calcoaceticus strains associated with UTI were significantly more resistant to netilmicin than were strains responsible for sepsis and pneumonia (83.3% vs 40.3% and 42.6%, respectively). The study confirmed that in addition to focused microbiologic surveillance, multiple-body-site monitoring can provide unique information about the sensitivity of the pathogens involved. The results suggest that antimicrobial resistance among nosocomial pathogens depends on the site of infection or the type of microbiologic specimen. Key words:antibiotic resistance, nosocomial infection, gram-negative bacteria, intensive care unit. 691
CLINICAL THERAPEUTICS*
INTRODUCTION Nosocomial infections are a common problem in modem medicine, particularly among patients treated in the intensive care unit (ICU). 1-3 Often caused by bacteria that are resistant to multiple antibiotics,4 these infections delay optimal antimicrobial treatment and adversely affect outcomes .5 While of crucial importance, the choice of empiric antibiotic therapy is often limited in countries with high rates of antibiotic resistance, 6-s necessitating the use of newer, more expensive antimicrobial agents. Because problems of resistance within hospitals are often specific to the ICU, empiric therapy should be based on the results of focused microbiologic surveillance. 9-H Such surveillance, however, relies on pooled data reflecting the antibiotic susceptibilities of multiple isolates obtained from various anatomic sites; thus the results may be misleading. 12 For optimal guidance in selecting empiric therapy, antibiotic susceptibilities of body-site-specific pathogens should be determined. 13 This study involved body-site monitoring of the pathogens responsible for nosocomial sepsis, pneumonia, and urinary tract infections (UTIs) in critically ill patients treated in the ICU. We began with the hypothesis that gram-negative pathogens isolated from different body sites differ in their antibiotic susceptibility patterns. PATIENTS AND METHODS This prospective, 6-year study (January 1, 1990, to December 31, 1995) involved 622 patients treated in our ICU for more than 48 hours because of a life-threatening nosocomial infection. The infections were
692
defined according to criteria established by the Centers for Disease Control and Prevention. 14
Bacteriologic Assessment The frequency with which particular organisms were isolated in nosocomial infections of the bloodstream, respiratory tract, and urinary tract, as well as their antibiotic resistance, was assessed by examining cultures of specimens from the relevant body site. Specimens included tracheal aspirates or bronchial microlavage samples, blood from a peripheral vein and/or indwelling central venous catheter, and urine, respectively. 15 We used only the initial isolates of identified organisms. To avoid statistical bias, if the same pathogen was isolated from the bloodstream and from the urine or tracheal aspirates, it was regarded as the cause of the UTI or pneumonia but not of the sepsis. 13 Blood samples were obtained at the onset of a new febrile episode. When blood cultures grew common contaminants-Corynebacterium, Bacillus species, coagulase-negative staphylococci, or Propionibacterium acnes--at least two blood cultures had to be positive for the same organism within a 24-hour period for the case to be regarded as true bacteremia. 16 Tracheal aspiration and bronchial microlavage were performed through a sterile catheter when respiratory infection was suspected. All urine cultures testing positive for significant UTI (>105 bacteria/mL of urine) were included. Urine was taken once weekly. Specimens were cultured and bacteria identified using standard microbiologic techniques. Antibiotic susceptibility was determined by disk diffusion.
B. BARSI~ ET AL.
Statistical Analysis
The chi-square test was used to evaluate the statistical significance of observed differences in antibiotic susceptibility of the gram-negative pathogens isolated in the three types of nosocomial infection studied. Continuous variables were tested by using the Scheff6 test. ~S~TS Six hundred thirty-five bacterial isolates from patients with nosocomial infections were tested in the course of the study. Table I lists the species and distribution of the infecting organisms. Gram-negative bacteria were the predominant isolates, causing 65% of cases of sepsis, 78.7% of pneumonias, and 70.2% of UTIs. Acinetobacter calcoaceticus (baumannii), Pseudomonas aeruginosa, and Klebsiella
pneumoniae were the most frequently identified pathogens, except among UTIs, where Enterococcus species were found more often than A caicoaceticus. The respiratory tract was the most fertile source of bacteria. The gram-negative pathogens were highly resistant to all the antimicrobial agents commonly used in our ICU except for imipenem (Table II). The isolates associated with primary bloodstream infections (sepsis) were significantly less resistant to netilmicin and ciprofloxacin than were those responsible for respiratory tract infections and UTIs. The isolates causing UTIs were more sensitive to cefotaxime and ceftriaxone than were those associated with sepsis and pneumonia. The pathogens that caused pneumonia were less resistant to ceftazidime and more resistant to imipenem than were those that caused the other two types of
Table I. Microorganisms associated with nosocomial infections. No. (%) of Isolates
Microorganism Escherichia coli Klebsiella pneumoniae Citrobacterfreundii Serratia marcescens Proteus mirabilis Enterobacter sp Pseudomonas aeruginosa Acinetobacter calcoaceticus Other gram-negative organisms Enterococcus sp Staphylococcus aureus Other staphylococci Candida sp Other gram-positive organisms
Sepsis (251)
Pneumonia (253)
Urinary Tract Infections (131)
2 (0.8) 36 (14.3) 1 (0.4) 5 (2.0) 1 (0.4) 12 (4.8) 39 (15.5) 62 (24.7) 5 (2.0) 29 (11.6) 13 (5.2) 25 (10.0) 18 (7.2) 3 (1.2)
5 (2.0) 35 (13.8) 2 (0.8) 1 (0.4) 6 (2.4) 7 (2.8) 84 (33.2) 54 (21.3) 5 (2.0) 5 (2.0) 30 (11.9) 9 (3.6) 5 (2.0) 5 (2.0)
4 (3.1) 27 (20.6) 2 (1.5) 4 (3.1) 9 (6.9) 33 (25.2) 12 (9.2) 1 (0.8) 17 (13.0) 1 (0.8) 21 (16.0) -
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Table II. Resistance rates among gram-negative isolates causing nosocomial infections. No. (%) of Resistant Isolates
Antibiotic Gentamicin Netilmicin Amikacin Cefotaxime Ceftriaxone Ceftazidime Ciprofioxacin Pefloxacin Imipenem
Sepsis (163)
Pneumonia (199)
Urinary Tract Infections (92)
P
134 (82.2) 72 (44:2) 95 (58.3) 144 (88.3) 136 (83.4) 120 (73.6) 70 (42.9) 125 (76.7) 11 (6.7)
156 (78.4) 107 (53.8) 116 (58.3) 165 (82.9) 161 (80.9) 116 (58.3) 117 (58.8) 165 (82.9) 27 (13.6)
80 (87.0) 61 (66.3) 49 (53:2) 68 (73.9) 61 (66.3) 59 (64.1) 58 (63.0) 76 (82.6) 1 (1.1)
NS 0.0029 NS 0.0129 0.0036 0.0042 0.0005 NS 0.0531
infection, although imipenem resistance did not approach statistical significance. When resistance rates of Kpneumoniae, P aeruginosa, and A calcoaceticus were evaluated (Tables III to V), K pneumoniae associated with pneumonia and sepsis was less resistant to ciprofloxacin than were isolates from urine. A calcoaceticus associated with pneumonia and sepsis was less resistant to netilmicin than were strains causing UTI. P aeruginosa strains responsible for pneumonia were less resistant to ceftazidime than were isolates causing sepsis and UTI, although the difference was not statsfically significant (P = 0.1413). Resistance among the three major gram-negative pathogens was also tested without regard to their clinical relevance (Tables VI to VIII). Respiratory tract isolates of K pneumoniae were significantly less resistant to all three aminoglycosides than were those from blood or urine (P = 0.0293 for gentamicin, P =.0.0002 for netilmicin, and P = 0.0472 for amikacin). Urinary isolates were more resistant to 694
ciprofloxacin. Probably because of the small numbers of blood isolates of K pneumoniae, statistical significance was not achieved (P = 0.909). P aeruginosa strains from the respiratory tract were more sensitive to gentamicin, netilmicin, and ciprofioxacin than were those from blood or urine. A calcoaceticus strains from the blood and respiratory tract showed less resistance to netilmicin than did those from urine. Most strains of this pathogen (98%) were further classified as
A baumannii. The average ICU stay until the onset of nosocomial infection and isolation of pathogens was 25 days for sepsis, 15 days for pneumonia, and 31 days for UTI (P < 0.001). DISCUSSION AND C O N C L U S I O N S Monitoring microbial frequency and susceptibility patterns is a major component of infection control programs in medical facilities and is the first step toward se-
B. BARSI(2 ET AL.
Table III. Resistance rates among infection-causing Klebsiella pneumoniae isolates. No. (%) of Resistant Isolates
Antibiotic Gentamicin Netilmicin Amikacin Cefotaxime Ceftriaxone Ceftazidime Ciprofloxacin Pefloxacin Imipenem
Sepsis (36)
Pneumonia (35)
Urinary Tract Infections (27)
P
30 (83.3) 14 (38.9) 23 (63.9) 28 (77.8) 26 (72.2) 28 (77.8) 5 (13.9~ 27 (75.0) 1 (2.8)
25 (71.4) 12 (34.3) 19 (54.3) 22 (62.8) 22 (62.8) 19 (54.3) 8 (22.8) 21 (60.0) 1 (2.9)
25 (92.6) 14 (51.8) 18 (66.7) 20 (74.1) 17 (63.0) 20 (74.1) 12 (44.4) 22 (81.5) 1 (3.7)
NS NS NS NS NS NS 0.0204 NS *
*Not done because of low number in cell. Table IV. Resistance rates among infection-causing Pseudomonas aeruginosa isolates. No. (%) of Resistant Isolates
Antibiotic Gentamicin Netilmicin Amikacin Cefotaxime Ceftriaxone Ceftazidime Ciprofloxacin Pefloxacin Imipenem
Sepsis (39)
Pneumonia (84)
Urinary Tract Infections (33)
P
31 (79.5) 25 (64.1) 16 (41.0) 35 (89.7) 34 (87.2) 20 (51.3) 23 (59.0) 34 (87.2) 9 (23.1)
77 (91.7) 55 (65.5) 42 (50.0) 73 (86.9) 70 (83.3) 30 (35.7) 55 (65.5) 73 (86.9) 17 (20.2)
27 (81.8) 26 (78.8) 18 (54.5) 26 (78.8) 26 (78.8) 17 (51.5) 26 (78.8) 28 (84.8) -
NS NS NS NS NS NS NS NS NS
lecting the best antibiotic for empiric therapy. In addition to unit-specific surveillance, monitoring by infection site may help facilitate choosing the most appropriate antimicrobial agent. 12,17 Since 1988, our ICU has carded out focal surveillance using specimens obtained
from peripheral veins or central venous catheters, tracheal aspirate or bronchial microlavage samples, urine, and gastric secretions (data not presented). Preliminary results of body-site monitoring had suggested differences in the antibiotic resistance of gram-negative pathogens ac695
CLINICAL THERAPEUTICS®
Table V. Resistance rates among infection-causing Acinetobacter calcoaceticus isolates. No. (%) of Resistant Isolates
Antibiotic Gentamicin Netilmicin Amikacin Cefotaxime Ceftriaxone Ceftazidime Ciprofloxacin Pefloxacin Imipenem
Sepsis (62)
Pneumonia (54)
Urinary Tract Infections (12)
57 (91.9) 25 (40.3) 45 (72.6) 60 (96.8) 58 (93.5) 58 (93.5) 39 (62.9) 51 (82.3) -
50 (92.6) 23 (42.6) 40 (74.1) 52 (96.3) 52 (96.3) 51 (94.4) 41 (75.9) 52 (96.3) 1 (1.9)
12 (100) 10 (83.3) 6 (50.0) 12 (100) 11 (91.7) 10 (83.3) 10 (83.3) 12 (100) -
P NS 0.0255 NS NS NS NS NS 0.0361 -
Table VI. Resistance rates among infection-causing Klebsiella pneumoniae isolates regardless o f clinical relevance. No. (%) of Resistant Isolates
Antibiotic Gentamicin Netilmicin Amikacin Cefotaxime Ceftriaxone Ceftazidime Ciprofloxacin Pefloxacin Imipenem
Respiratory Secretions (89)
Blood (31 )
Urine (54)
P
64 (71.9) 23 (25.8) 41 (46.1) 53 (59.6) 54 (60.7) 55 (61.8) 15 (16.9) 53 (59.6) 1 (1.1)
28 (90.3) 13 (41.9) 20 (64.5) 24 (77.4) 22 (71.0) 24 (77.4) 3 (9.7) 24 (77.4) 1 (32)
48 (88.9) 30 (55.6) 35 (64.8) 35 (64.8) 33 (61.1) 38 (70.4) 15 (27.8) 38 (70.4) 1 (1.9)
0.0293 0.0002 0.0472 NS NS NS NS NS -
cording to the material analyzed. 7 To conf i n n these findings, we undertook this prospective, 6-year study in critically ill patients with nosocomial infections and found that gram-negative pathogens had different antibiotic resistance rates according to the type of nosocomial infection that was present. 696
Resistance to the most frequently used antimicrobial agents was extremely high in our ICU. The exception was imipenem, to which resistance was low in all types o f infection. If empiric therapy was selected solely on the basis of at least 85% inhibition of a given bacterial species, in our ICU only imipenem would be accept-
B. BARSIC ET AL.
Table VII. Resistance rates among Pseudomonas aeruginosa isolates regardless of clinical relevance. No. (%) of Resistant Isolates
Antibiotic Gentamicin Netilmicin Amikacin Cefotaxime Ceftriaxone Ceftazidime Ciprofloxacin Pefloxacin Imipenem
Respiratory Secretions (177)
Blood (22)
Urine (48)
P
102 (57.6) 89 (50.3) 65 (36.7) 140 (79.1) 127 (71.8) 55 (31.1) 98 (55.4) 138 (78.0) 25 (14.1)
16 (72.7) 15 (68.2) 10 (45.5) 19 (86.4) 18 (81.8) 9 (40.9) 13 (59.1) 20 (90.9) 3 (13.6)
40 (83.3) 37 (77.1) 26 (54.2) 42 (87_5) 38 (79.2) 21 (43.8) 39 (81.3) 43 (89.6) 3 (6.3)
0.0030* 0.0021 0.0837 NS NS NS 0.0049 NS NS
*Respiratorysecretionswere comparedwith urine becausefewerthan five sensitive strains were isolatedfromblood. Table VIII. Resistance rates among Acinetobacter calcoaceticus isolates regardless of clinical relevance. No. (%) of Resistant Isolates
Antibiotic Gentamicin Netilmicin Amikacin Cefotaxime Ceftriaxone Ceftazidime Ciprofloxacin Pefloxacin Imipenem
Respiratory Secretions (142)
Blood (50)
Urine (35)
P
129 (90.8) 41 (28.9) 111 (78.2) 133 (93.7) 133 (93.7) 131 (92.3) 105 (73.9) 129 (90.8) 2 (1.4)
45 (90.0) 19 (38.0) 38 (76.0) 48 (96.0) 48 (96.0) 48 (96.0) 33 (66.0) 42 (84.0) 1 (2.0)
34 (97.1) 22 (62.9) 25 (71.4) 33 (94.3) 32 (91.4) 32 (91.4) 28 (80.0) 32 (91.4) -
NS 0.0008 0.6948 NS NS NS NS NS -
able for all types o f nosocomial infections. Investigators in countries with much lower rates o f resistance in the ICU have made similar observations, is Analysis of susceptibility data over several years can readily identify changes in resistance patterns. Such changes were not demon-
strated in our study, except for the emergence of imipenem-resistant P aeruginosa strains. Despite that, the number of imipenem-resistant isolates did not significantly increase, probably because of the somewhat restricted use of this drug. Similar findings have been noted elsewhere. 193°
697
CLINICAL THERAPEUTICS"
Our study uncovered significant differences associated with the type of infection. Pathogens responsible for sepsis were less resistant to aminoglycosides, and those causing UTIs were less resistant to third-generation cephalosporins. Isolates in pneumonia were less resistant to ceftazidime, probably because P aeruginosa was frequently identified. However, few studies support our hypothesis. Gaynes and Culver 21 found higher imipenem resistance among gramnegative bacteria from the respiratory tract. In a Swedish study, 22 isolates from the blood generally were more sensitive to all cephalosporins than were isolates collected from urine and wounds during the same period. In our study, Pseudomonas species from the respiratory tract were less resistant to ceftazidime than were isolates from the blood, whereas Koonitz 12 found quite the opposite. When we selectively analyzed particular pathogens, differences in sensitivity to some antimicrobial agents were confirmed. Probably these differences were not more dramatic because of the low number of strains tested. The reason for the observed differences is not clear. The time of hospitalization could not have influenced the resuits, because there was no uniform pattern of differences in antibiotic sensitivity. It is possible that the rate of selection of resistant pathogens differs among materials because of differences in local antibiotic concentrations, but this remains to be proved. Our study confirmed that in addition to focused microbiologic surveillance, monitoring of multiple body sites can provide valuable information about the antibiotic sensitivity of the pathogens involved. Our results suggest that antimicrobial resis698
tance among nosocomial pathogens depends on the site of infection (or type of microbiologic specimen), as well as on noncritical antibiotic use, type of ICU, and type and size of hospital. Multicenter studies in countries with low or medium rates of antibiotic resistance may further clarify this issue, and even greater differences in antibiotic sensitivity based on the site of infection may be seen. Composite antibiograms should be developed from the individual minimum inhibitory concentrations of bodysite--specific nosocomial pathogens. 4,13
ACKNOWLEDGMENTS Publication of this paper is sponsored by Merck & Co., Inc. The research was partially supported by a grant from the Croatian Ministry of Science.
Address correspondence to: Bruno Bar, re, University Hospital for Infectious Diseases "dr Fran Mihaljevic," Zagreb, Croatia. REFERENCES
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